US7820654B2 - Pyrimidine compounds, process for their preparation and compositions containing them - Google Patents

Pyrimidine compounds, process for their preparation and compositions containing them Download PDF

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US7820654B2
US7820654B2 US11/234,695 US23469505A US7820654B2 US 7820654 B2 US7820654 B2 US 7820654B2 US 23469505 A US23469505 A US 23469505A US 7820654 B2 US7820654 B2 US 7820654B2
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phenyl
pyrimidin
ylamino
piperidin
carbon atoms
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US20060084645A1 (en
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Manojit Pal
Srinivas Kalleda
Srinivas Padakanti
Nalivela Kumara Swamy
Koteswar Rao Yeleswarapu
Christopher W. Alexander
Ish Khanna
Javed Iqbal
Sivaram Pillarisetti
Deepak Barange
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to substituted pyrimidine compounds, methods and compositions for making and using substituted pyrimidine compounds, and methods for preventing or treating diseases in humans or animals employing such compounds and compositions.
  • Novel compounds for new therapeutic interventions are needed for many areas of medicine and disease treatment.
  • chronic and acute inflammatory conditions form the basis for diseases affecting all organ systems including, but not limited to, asthma, acute inflammatory diseases, vascular inflammatory disease, chronic inflammation, atherosclerosis, angiopathy, myocarditis, nephritis, Crohn's disease, arthritis, type I and II diabetes and associated vascular pathologies.
  • the incidence of these inflammatory conditions is on the rise in the population as a whole, with diabetes alone affecting 16 million people. Therefore, synthesis of novel compounds leads to new possibilities for discovery of novel therapeutic interventions.
  • vascular smooth muscle cell proliferation is a common consequence of endothelial injury and is believed to be an early pathogenetic event in the formation of atherosclerotic plaques or complications related to vascular injury or as a result surgical interventions.
  • Abnormal vascular smooth muscle cell (SMC) proliferation is thought to contribute to the pathogenesis of vascular occlusive lesions, including arteriosclerosis, atherosclerosis, restenosis, and graft atherosclerosis after organ transplantation.
  • Glycated proteins Glycated proteins and advanced glycation end products (AGE) contribute to cellular damage, particularly, diabetic tissue injury.
  • AGE advanced glycation end products
  • hyperglycemia can be linked to microangiopathies is through the process of non-enzymatic glycation of critical proteins.
  • cancer Another major area of unwanted cellular growth, that is unchecked by the body's regulatory systems, is cancer or oncological conditions.
  • Many therapies have been used and are being used in an effort to restore health or at least stop the unwanted cell growth.
  • therapeutic agents can have an effect individually, but often, therapeutic regimes require combinations of different pharmacological agents with treatments such as surgery or radiation.
  • the present invention is directed to novel pyrimidines, novel compositions comprising pyrimidines, and novel methods employing such pyrimidines and compositions.
  • Disclosed herein are methods for making pyrimidines, compositions comprising pyrimidines, and methods and compositions for using pyrimidines.
  • the pyrimidine compounds and compositions comprising the compounds have utility in treatment of a variety of diseases.
  • compounds in accordance with the present invention, and compositions comprising these compounds comprise nitrogen heterocyclic compounds of formula (II):
  • this disclosure provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula (II):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 in each occurrence, are independently >NR 5 , —(CH 2 )n-, —(CH 2 )p-(CH ⁇ CH)(CH 2 )q-, >CR 5 R 6 , —(CH 2 )p(C ⁇ C)(CH 2 )q-, —O—, >CO, —S—, >SO or >SO 2 ; wherein n, p, and q are independently an integer from 0 to 3;
  • R 5 and R 6 in each occurrence, are independently: 1) a substituted or an unsubstituted alkyl, aryl, alkoxyalkyl, heteroaryl, cycloalkyl, or heterocyclyl, any of which having up to about 10 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or 2) hydrogen;
  • R z wherein when Y 1 or Y 2 is independently —O— or —S—; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, aryl, alkoxyalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen;
  • R z wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, haloalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, alkoxy, alkenyl, alkynyl, alkoxyalkyl, aryl, —CO 2 R 5 , —COR 5 , heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen
  • R 3 and R 4 in each occurrence, are independently: 1) a substituted or an unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, haloalkyl, alkylthio, alkylsufonyl, aryl, —CO 2 R 5 , —COR 5 , —NR 5 R 6 , —SO 2 NR 5 R 6 , —SO 3 R 5 , heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; 2) hydrogen; halogen; hydroxyl; or cyano; or 3) Y 1 R 1 ;
  • any of R 1 , R 2 , R 5 , or R 6 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, N(R 8 ) 2 , —COR 9 , —OCOR 9 , —CON(R 8 ) 2 , —(CH 2 ) b —CO 2 R 8 wherein b is an integer from 0 to 3, —SO 2 R 9 , —OCO(CH 2 ) b COOR 10 , —NHSO 2 R 9 or —SO 2 N(R 8 ) 2 , any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, hydroxyl, or cyano;
  • R 8 in each occurrence, is independently: 1) an alkyl, a haloalkyl, or an aryl having up to about 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heteroaryl having up to about 8 carbon atoms R 9 is optionally substituted with halogen, hydroxyl, alkyl, alkoxy, carboxylic acid or its esters; and
  • any of R 3 or R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, —COR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —SR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or —N(R 10 ) 2 , any of which having up to about 10 carbon atoms; and
  • R 10 in each occurrence, is independently: 1) an alkyl or an aryl having up to about 6 carbon atoms; or hydrogen.
  • compounds in accordance with the present invention, and compositions comprising these compounds comprise nitrogen heterocyclic compounds of formula (II):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 in each occurrence, are independently represents —O—, —S—, >NR 5 , —(CH 2 )n-, —(CH 2 )p(C ⁇ C)(CH 2 )q-, wherein n, p, and q are independently represent 0;
  • the corresponding R z wherein z is 1 or 2, in each occurrence is independently selected from: a) a substituted or an unsubstituted alkyl, alkoxyalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO or >SO 2 , or b) hydrogen;
  • R 5 is hydrogen or alkyl
  • R 3 is hydrogen
  • R 4 is a substituted or an unsubstituted alkyl, aryl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, or 2) hydrogen, halogen, hydroxyl;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, —COR 9 , —OCOR 9 , —CON(R 8 ) 2 , —(CH 2 ) b CO 2 R 8 , —OCO(CH 2 ) b COOR 10 , wherein b is an integer from 0 to 3, —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 N(R 8 ) 2 , or 2) hydrogen, halogen or hydroxyl;
  • R 8 in each occurrence, is independently: 1) an alkyl, a haloalkyl, or an aryl having up to about 6 carbon atoms, or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heteroaryl. R 9 is optionally substituted with halogen, hydroxyl, alkyl, alkoxy, carboxylic acid or its esters;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, —COR 10 , —SR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or —N(R 10 ) 2 ; and
  • R 10 in each occurrence, is independently hydrogen, an alkyl, an aryl, heteroaryl or heterocyclyl.
  • the present invention is directed to methods and compositions comprising compounds that have utility in treatment of pathological conditions.
  • One aspect of the present invention comprises pyrimidines and compositions comprising pyrimidines in methods for treating diseases related to unwanted cellular proliferation.
  • Vascular diseases such as cardiovascular diseases, organ transplant sequellae, vascular occlusive conditions including, but not limited to, neointimal hyperplasia, restenosis, transplant vasculopathy, cardiac allograft vasculopathy, atherosclerosis, and arteriosclerosis, are caused by or have collateral damage due to unwanted cellular proliferation, such as smooth muscle cell (SMC) hyperplasia.
  • SMC smooth muscle cell
  • At least one activity of one or more of these compounds is that the compound has the activity of affecting the synthesis of proteoglycans including induction and synthesis of proteoglycans and active fragments of proteoglycans.
  • Methods comprise administration of compositions comprising compounds that have at least the activity of affecting cellular proliferation and affecting proteoglycan synthesis and activity.
  • the pyrimidines and compositions comprising pyrimidines disclosed herein can be employed to prevent or treat the aforementioned diseases.
  • the present invention also comprises methods and compositions comprising pyrimidines described herein that have an activity associated with modulation of glycosidase enzymes and thus, affecting the substrates for such enzymes.
  • Glycosidase enzymes and their activity with their substrates, such as proteoglycans or glycated proteins, are aspects of a variety of diseases such as vascular conditions, proteoglycan-associated diseases, kidney disease, autoimmune disease and inflammatory diseases.
  • Pyrimidines described herein that have an activity that affects the concentrations of substrates of glycosidase enzymes are used in methods of treatment of such vascular, inflammatory, metastatic and systemic diseases.
  • Another aspect of the present invention comprises methods and compositions comprising pyrimidines of the present invention for the treatment and prevention of conditions or diseases that have as an aspect of the disease or condition, inflammation.
  • An aspect of the present invention is directed to methods and compositions comprising pyrimidines that are effective in inhibiting inflammation, particularly inflammation associated with the accumulation or presence of glycated proteins or AGE.
  • Methods of treatment comprise administration of compositions comprising pyrimidines having at least the activity of modulating inflammatory reactions that are components of biological conditions including, but not limited to, vascular complications of type I and type II diabetic-induced vasculopathies, other vasculopathies, microangiopathies, renal insufficiency, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis.
  • An aspect of the present invention also comprises methods and compositions for the treatment of diseases, preconditions or pathologies associated with inflammatory cytokines and other inflammation related molecules.
  • the present invention also comprises pharmaceutical compositions comprising the compounds disclosed herein. Routes of administration and dosages of effective amounts of the compounds and pharmaceutical compositions are also disclosed.
  • the compounds of the present invention can be administered in combination with other pharmaceutical agents in a variety of protocols for effective treatment of disease.
  • the present invention relates to drug delivering or eluting medical devices that contain or are coated with at least one compound disclosed herein.
  • the medical device suitable for use with the compounds of the present invention include, but are not limited to, stents and other medical devices that can provide a substrate for delivery of at least one compound.
  • novel pyrimidine compounds and novel compositions comprising pyrimidine compounds are described herein.
  • compounds in accordance with the present invention, and compositions comprising these compounds comprise substituted pyrimidine compounds of formula (II):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 in each occurrence, are independently >NR 5 , —(CH 2 )n-, —(CH 2 )p-(CH ⁇ CH)(CH 2 )q-, >CR 5 R 6 , —(CH 2 )p(C ⁇ C)(CH 2 )q-, —O—, >CO, —S—, >SO or >SO 2 ; wherein n, p, and q are independently an integer from 0 to 3;
  • R 5 and R 6 in each occurrence, are independently: 1) a substituted or an unsubstituted alkyl, aryl, alkoxyalkyl, heteroaryl, cycloalkyl, or heterocyclyl, any of which having up to about 10 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or 2) hydrogen;
  • R z wherein when Y 1 or Y 2 is independently —O— or —S—; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, aryl, alkoxyalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen;
  • R z wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, haloalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, alkoxy, alkenyl, alkynyl, alkoxyalkyl, aryl, —CO 2 R 5 , —COR 5 , heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen
  • R 3 and R 4 in each occurrence, are independently: 1) a substituted or an unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, haloalkyl, alkylthio, alkylsufonyl, aryl, —CO 2 R 5 , —COR 5 , —NR 5 R 6 , —SO 2 NR 5 R 6 , —SO 3 R, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; 2) hydrogen; halogen; hydroxyl; or cyano; or 3) Y 1 R 1 ;
  • any of R 1 , R 2 , R 5 , or R 6 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, N(R 8 ) 2 , —COR 9 , —OCOR 9 , —CON(R 8 ) 2 , —(CH 2 ) b —CO 2 R 8 wherein b is an integer from 0 to 3, —SO 2 R 9 , —OCO(CH 2 ) b COOR 10 , —NHSO 2 R 9 or —SO 2 N(R 8 ) 2 , any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, hydroxyl, or cyano;
  • R 8 in each occurrence, is independently: 1) an alkyl, a haloalkyl, or an aryl having up to about 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heteroaryl having up to about 8 carbon atoms R 9 is optionally substituted with halogen, hydroxyl, alkyl, alkoxy, carboxylic acid or its esters; and
  • any of R 3 or R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, —COR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —SR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or —N(R 10 ) 2 , any of which having up to about 10 carbon atoms; and
  • R 10 in each occurrence, is independently: 1) an alkyl or an aryl having up to about 6 carbon atoms; or hydrogen.
  • this disclosure provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula (IIi):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 in each occurrence, are independently >NR 5 , —(CH 2 )n- wherein n is 0 or 1, —S—, —O—, >CO, or >SO 2 ;
  • R 5 in each occurrence, is independently: 1) a substituted or an unsubstituted alkyl, aryl, alkoxyalkyl, heteroaryl, cycloalkyl, or heterocyclyl, any of which having up to about 10 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or 2) hydrogen;
  • R z wherein when Y 1 or Y 2 is independently —O— or —S—; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, aryl, alkoxyalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen;
  • R z wherein when Y 1 or Y 2 is independently —(CH 2 )n-, >CO, or >SO 2 ; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, haloalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, alkoxy, alkenyl, alkynyl, alkoxyalkyl, aryl, —CO 2 R 5 , —COR 5 , heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, cyano, or hydroxyl;
  • R 3 and R 4 in each occurrence, are independently: 1) haloalkyl having less than 3 carbon atoms; 2) alkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl having up to about 10 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; 3) hydrogen; or 4) Y 1 R 1 ;
  • R 1 , R 2 , or R 5 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, N(R 8 ) 2 , —SO 2 R 9 , or —SO 2 N(R 8 ) 2 , any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, or cyano;
  • R 8 in each occurrence, is independently: 1) an alkyl, a haloalkyl, or an aryl having up to about 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heteroaryl having up to about 8 carbon atoms;
  • any of R 3 or R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, —COR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —SR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or —N(R 10 ) 2 , any of which having up to about 10 carbon atoms; and
  • R 10 in each occurrence, is independently: 1) an alkyl or an aryl having up to about 6 carbon atoms; or hydrogen.
  • this disclosure provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula (IIii):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric miixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 are, in each occurrence, independently selected from >NR 5 , >(CH 2 ) n wherein n is 0 or 1, —O—, >CO, or >SO 2 ;
  • R 5 in each occurrence, is independently: 1) a substituted or an unsubstituted alkyl, aryl, alkoxyalkyl, heteroaryl, cycloalkyl, or heterocyclyl, any of which having up to about 10 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or 2) hydrogen;
  • R z wherein when Y 1 or Y 2 is independently —O—; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, aryl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen; and
  • R z wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, haloalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, alkoxy, aryl, or heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, cyano, or hydroxyl;
  • R 3 and R 4 in each occurrence are independently: 1) haloalkyl having less than 3 carbon atoms; 2) alkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl having up to about 10 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; 3) hydrogen; or 4) Y 1 R 1 ;
  • R 1 , R 2 , or R 5 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, N(R 8 ) 2 , —SO 2 R 9 , or —SO 2 N(R 8 ) 2 , any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, or cyano;
  • any of R 3 or R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, haloalkyl, —SO 2 R 10 , —SR 10 , —SO 2 N(R 10 ) 2 , or —N(R 10 ) 2 , any of which having up to about 10 carbon atoms; and
  • R 8 , R 9 , and R 10 in each occurrence, are independently: 1) an alkyl or an aryl having up to about 6 carbon atoms; or 2) hydrogen.
  • the present invention provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula (IIiii):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 are, in each occurrence, independently >NR 5 , >(CH 2 )n wherein n is 0 or 1, or —O—;
  • R 5 in each occurrence, is independently: 1) an alkyl, an aryl, an alkoxyalkyl, a heteroaryl, a cycloalkyl, or a heterocyclyl, any of which having up to about 10 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or 2) hydrogen;
  • R z wherein when Y 1 or Y 2 is independently —O—; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, aryl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen; and
  • Y 1 or Y 2 is independently —(CH 2 )n-; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, haloalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, alkoxy, aryl, or heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, cyano, or hydroxyl;
  • R 1 , R 2 , or R 5 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, N(R 8 ) 2 , —SO 2 R 9 , or —SO 2 N(R 8 ) 2 , any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, or cyano;
  • R 8 and R 9 in each occurrence, are independently: 1) an alkyl or an aryl having up to about 6 carbon atoms; or 2) hydrogen;
  • R 3 is hydrogen or halogen
  • R 4 in each occurrence, is independently: 1) haloalkyl having less than 3 carbon atoms; 2) alkyl, aryl, —COR 5 , cycloalkyl, heteroaryl, or heterocyclyl having up to about 10 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; 3) hydrogen; or 4) Y 1 R 1 .
  • the present invention provides for compounds and compositions comprising these compounds, wherein the compounds have the following formula (IIiv):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 are, in each occurrence, independently >NR 5 , >(CH 2 ), wherein n is 0 or 1,or —O—;
  • R 5 in each occurrence, is independently: 1) an alkyl, an aryl, a cycloalkyl, or a heteroaryl or a heterocyclyl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen;
  • R z wherein when y 1 or Y 2 is independently —(CH 2 )n- or —O—; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, aryl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen;
  • R 1 , R 2 , or R 5 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, N(R 8 ) 2 , —SO 2 R 9 , or —SO 2 N(R 8 ) 2 , any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, or cyano;
  • R 8 and R 9 in each occurrence, are independently: 1) an alkyl or an aryl having up to about 6 carbon atoms; or 2) hydrogen; and
  • R 3 and R 4 are, in each occurrence, independently: 1) R 1 or 2) Y 1 R 1 .
  • Another aspect of the present invention encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula (IIv):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 are, in each occurrence, independently >NR 5 , >CH 2 , or —O—;
  • R 5 in each occurrence, is independently: 1) an alkyl, an aryl, a cycloalkyl, or a heteroaryl or a heterocyclyl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen;
  • R z wherein when Y 1 or Y 2 is independently >CH 2 or —O—; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) a substituted or an unsubstituted alkyl, aryl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms; or 2) hydrogen; and
  • R 3 and R 4 in each occurrence, are independently: 1) R 1 or 2) Y 1 R 1 .
  • this invention provides compounds and compositions comprising these compounds, wherein the compounds have the following formula (IIvi):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y z is 1 or 2
  • z is 2 or 1, respectively, is >(CH 2 ) n wherein n is 0 or 1;
  • Y z is >(CH 2 ) n
  • the corresponding R z wherein z is 2 or 1
  • R z is >NH
  • the corresponding R z is 1 or 2
  • R 1 or R 2 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, N(R 8 ) 2 , —COR 9 , —OCOR 9 , —CON(R 8 ) 2 , —CO 2 R 9 , —SO 2 R 9 , —OCO(CH 2 ) b COOR 10 , —NHSO 2 R 9 or —SO 2 N(R 8 ) 2 , any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, or cyano;
  • R 8 and R 9 in each occurrence, are independently: 1) an alkyl or an aryl having up to about 6 carbon atoms; or 2) hydrogen; and
  • R 3 is hydrogen
  • R 4 is R 1 or Y 1 R 1 .
  • R z when Y z is >NH, wherein z is 1 or 2, the corresponding R z can be phenyl, naphthyl, pyridyl, or benzoxazolyl;
  • R z when Y z is >(CH 2 ) n , wherein z is 2 or 1, respectively, the corresponding R z can be phenyl, naphthyl, benzoxazolyl, pyridyl, pyrazolyl, isoxazolyl, pyrazinyl, imidazopyridinyl, benzdioxolanyl, morpholinyl, piperazinyl, or piperidinyl.
  • this disclosure encompasses compounds and compositions comprising these compounds, wherein the compounds have the following formula (IIvii):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 are, in each occurrence, independently >(CH 2 )n wherein n is 0 or 1;
  • R 1 and R 2 are independently selected from a substituted or an unsubstituted: 1) aryl; or 2) heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to about 10 carbon atoms;
  • R 1 or R 2 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, N(R 8 ) 2 , —COR 9 , —OCOR 9 , —CON(R 8 ) 2 , —CO 2 R 9 , —SO 2 R 9 , —OCO(CH 2 ) b COOR 10 , —NHSO 2 R 9 or —SO 2 N(R 8 ) 2 , any of which having up to about 10 carbon atoms; or 2) hydrogen, halogen, or cyano;
  • R 8 and R 9 in each occurrence, are independently: 1) an alkyl or an aryl having up to about 6 carbon atoms; or 2) hydrogen; and
  • R 3 is hydrogen or halogen
  • R 4 is R 1 or Y 1 R 1 .
  • R 1 and R 2 of the formula (IIvii) can be independently phenyl, naphthyl, benzoxazolyl, pyridyl, pyrazolyl, isoxazolyl, pyrazinyl, imidazopyridinyl, benzdioxolanyl, morpholinyl, piperazinyl, or piperidinyl.
  • this disclosure further provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula (IIviii):
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 in each occurrence, are independently represents —O—, —S—, >NR 5 , —(CH 2 )n-, —(CH 2 )p(C ⁇ C)(CH 2 )q-, wherein n, p, and q are independently represent 0;
  • the corresponding R z wherein z is 1 or 2, in each occurrence is independently selected from: a) a substituted or an unsubstituted alkyl, alkoxyalkyl, cycloalkyl, —COR 9 , aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO or >SO 2 , or b) hydrogen;
  • R 5 is hydrogen or alkyl
  • R 3 is hydrogen
  • R 4 is a substituted or an unsubstituted alkyl, aryl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, or 2) hydrogen, halogen, hydroxyl;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, —COR 9 , —OCOR 9 , —CON(R 8 ) 2 , —(CH 2 ) b CO 2 R 8 , —OCO(CH 2 ) b COOR 10 , wherein b is an integer from 0 to 3, —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 N(R 8 ) 2 , or 2) hydrogen, halogen or hydroxyl;
  • R 8 in each occurrence, is independently: 1) an alkyl, a haloalkyl, or an aryl having up to about 6 carbon atoms, or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heteroaryl. R 9 is optionally substituted with halogen, hydroxyl, alkyl, alkoxy, carboxylic acid or its esters;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, —COR 10 , —SR 10 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or —N(R 10 ) 2 ; and
  • R 10 in each occurrence, is independently hydrogen, an alkyl, an aryl, heteroaryl or heterocyclyl.
  • Y 1 and Y 2 in each occurrence, can be independently >NR 5 , —(CH 2 )n-, —(CH 2 )p-(C ⁇ C)(CH 2 )q-, wherein n, p, and q are independently represent 0;
  • R 1 and R 2 in each occurrence is independently selected from a substituted or an unsubstituted cycloalkyl, aryl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S— or >CO;
  • R 5 is hydrogen
  • R 3 is hydrogen
  • R 4 is a substituted or an unsubstituted aryl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, —COR 9 , —OCOR 9 , —CON(R 8 ) 2 , —(CH 2 ) b CO 2 R , —OCO(CH 2 ) b COOR 10 , wherein b is an integer from 0 to 3, —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 N(R 8 ) 2 ; or 2) hydrogen, halogen or hydroxyl;
  • R 8 in each occurrence, is independently: 1) an alkyl, a haloalkyl, or an aryl having up to about 6 carbon atoms, or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heteroaryl. R 9 is optionally substituted with halogen, hydroxyl, alkyl, alkoxy, carboxylic acid or its esters;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, —COR 10 , —SR 10 , —SO 2 R 10 or —SO 2 N(R 10 ) 2 ; and
  • R 10 in each occurrence, is independently hydrogen, an alkyl, an aryl or heterocyclyl.
  • Y 1 and Y 2 in each occurrence, can independently represents —(CH 2 )n-, wherein n is 0;
  • R 1 is a substituted or an unsubstituted aryl, heteroaryl or heterocycle comprising at least one heteroatom selected from —O—, >N— or —S—; where in the carbon atom of the said heterocycle or heteroaryl is connected to the carbon atom of the pyrimidine ring;
  • R 2 is a substituted or an unsubstituted nitrogen containing heterocyclyl, which may optionally further contain at least one more heteroatom selected from —O—, >N— or —S—, wherein the nitrogen atom of the said heterocycle is connected to the carbon atom of the pyrimidine ring;
  • R 4 is a substituted or an unsubstituted aryl or heteroaryl
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkoxy, haloalkyl, haloalkoxy;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy or —SO 2 R 10 ;
  • R 10 is an alkyl or an aryl having up to about 6 carbon atoms.
  • Y 1 and Y 2 in each occurrence, can be independently represents —(CH 2 )n-, wherein n is 0;
  • R 1 is a substituted or an unsubstituted nitrogen containing heterocyclyl, which may optionally further contain at least one more heteroatom selected from —O—, >N— or —S—, wherein the nitrogen atom of the said heterocycle is connected to the carbon atom of the pyrimidine ring;
  • R 2 is a substituted or an unsubstituted aryl, heteroaryl or heterocyclyl comprising at least one heteroatom selected from —O—, >N— or —S—, wherein the carbon atom of the said heteroaryl or heterocycle is connected to the carbon atom of the pyrimidine ring;
  • R 4 is a substituted or an unsubstituted aryl or heteroaryl
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl or haloalkoxy;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, or —SO 2 R 10 ;
  • R 10 is an alkyl or an aryl.
  • Y 1 represents —(CH 2 )n-, wherein n is 0;
  • Y 2 represents NH
  • R 1 and R 2 in each occurrence is independently selected from a substituted or an unsubstituted aryl or heteroaryl;
  • R 4 is a substituted or an unsubstituted nitrogen containing heterocyclyl, which may optionally further contain at least one more heteroatom selected from —O—, >N— or —S—, wherein the nitrogen atom of the heterocycle ring is connected to the carbon atom of the pyrimidine ring;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, —SO 2 R 9 , or —SO 2 N(R 8 ) 2 ;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl or alkoxy;
  • R 8 is hydrogen, an alkyl, a haloalkyl, or an aryl
  • R 9 is an alkyl, a haloalkyl, an aryl, or a heteroaryl.
  • this disclosure also provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 and R 2 in each occurrence is independently selected from a substituted or an unsubstituted cycloalkyl, aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N— or —S—;
  • R 4 is a substituted or an unsubstituted nitrogen containing heterocyclyl or heteroaryl, which may optionally firther contain at least one more heteroatom selected from —O—, >N— or —S—, wherein the nitrogen atom of the said heterocycle or heteroaryl is connected to the carbon atom of the pyrimidine ring;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl or haloalkoxy;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl or alkoxy.
  • R 1 and R 2 in each occurrence can be independently selected from a substituted or an unsubstituted cycloalkyl or aryl;
  • R 4 can be a substituted or an unsubstituted nitrogen containing heterocyclyl, which may optionally further contain at least one more heteroatom selected from —O—, >N— or —S—, wherein the nitrogen atom of the said heterocycle is connected to the carbon atom of the pyrimidine ring;
  • R 1 and R 2 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl or alkoxy;
  • R 4 is optionally substituted with at least one group independently selected from hydroxyl or alkoxy.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 represents NH or —(CH 2 )n-, wherein n is 0;
  • R 1 and R 2 in each occurrence is independently selected from a substituted or an unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N— or —S—;
  • R 4 is a substituted or an unsubstituted aryl
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, —SO 2 R 9 or —SO 2 N(R 8 ) 2 ;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkoxy, —COR 9 , —SR 9 or —SO 2 R 9 ;
  • R 8 in each occurrence, is independently hydrogen, an alkyl, a haloalkyl, or an aryl;
  • R 9 is an alkyl, a haloalkyl, an aryl or a heteroaryl.
  • Y 1 can be —(CH 2 )n-, wherein n is 0;
  • R 1 is a substituted or an unsubstituted nitrogen containing heterocyclyl, which may optionally further contain at least one more heteroatom selected from —O—, >N— or —S—, wherein the nitrogen atom of the said heterocycle is connected to the carbon atom of the pyrimidine ring;
  • R 2 is a substituted or an unsubstituted aryl, aralkyl, heteroaryl, heterocyclyl, which may optionally further contain at least one more heteroatom comprising at least one heteroatom selected from —O—, >N— or —S—;
  • R 4 is a substituted or an unsubstituted aryl, heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O—, >N— or —S—;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, —SO 2 R 9 or —SO 2 N(R 8 ) 2 ;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkoxy or —SO 2 R 9 ;
  • R 8 in each occurrence, is independently hydrogen, an alkyl, a haloalkyl, or an aryl;
  • R 9 is an alkyl, a haloalkyl, an aryl, or a heteroaryl.
  • Y 1 can represent —(CH 2 )n-, wherein n is 0;
  • R 1 is morpholinyl or hydroxyl substituted piperidinyl, thiomorpholinyl, piperazinyl, wherein the nitrogen atom of the said heterocycle is connected to the carbon atom of the pyrimidine ring;
  • R 2 is a substituted or an unsubstituted aryl
  • R 4 is a substituted or an unsubstituted aryl
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkoxy, haloalkyl or haloalkoxy;
  • R 4 is optionally substituted with at least one group independently selected from halogen, alkoxy or haloalkoxy.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formulas:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 2 represents NH or —(CH 2 )n-, wherein n is 0;
  • R 1 and R 2 in each occurrence is independently selected from a substituted or an unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO or >SO 2 ;
  • R 4 is a substituted or an unsubstituted aryl
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, —COR 9 , —SO 2 R 9 or —SO 2 N(R 8 ) 2 ;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl or alkoxy;
  • R 8 is hydrogen, an alkyl, a haloalkyl, or an aryl
  • R 9 is an alkyl, a haloalkyl, an aryl, or a heteroaryl.
  • Y 2 represents —(CH 2 )n-, wherein n is 0;
  • R 1 is a substituted or an unsubstituted aryl, aralkyl, heteroaryl, heterocyclyl, which may optionally further contain at least one more heteroatom comprising at least one heteroatom selected from —O—, >N—, —S— or >SO 2 ;
  • R 2 is a substituted or an unsubstituted nitrogen containing heterocyclyl, heteroaryl which may optionally further contain at least one more heteroatom selected from —O—, >N— or —S—, wherein the nitrogen atom of the said heterocycle is connected to the carbon atom of the pyrimidine ring;
  • R 4 is a substituted or an unsubstituted aryl
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, —COR 9 , —SO 2 R 9 or —SO 2 N(R 8 ) 2 ;
  • R 4 is optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl or alkoxy;
  • R 8 is hydrogen, an alkyl, a haloalkyl, or an aryl
  • R 9 is an alkyl, a haloalkyl, an aryl, or a heteroaryl.
  • Y 2 represents —(CH 2 )n-, wherein n is 0;
  • R 1 is a substituted or an unsubstituted aryl
  • R 2 is a morpholinyl, piperazinyl, thiomorpholinyl, piperidinyl, wherein the nitrogen atom of the said heterocycle is connected to the carbon atom of the pyrimidine ring;
  • R 4 is a substituted or an unsubstituted aryl
  • R 1 and R 2 are optionally substituted with at least one group independently selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, —COR 9 , —SO 2 R 9 or —SO 2 N(R 8 ) 2 ;
  • R 4 is optionally substituted with at least one group independently selected from halogen or alkoxy;
  • R 8 is hydrogen, an alkyl, a haloalkyl, or an aryl
  • R 9 is an alkyl, a haloalkyl, an aryl, or a heteroaryl.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 are selected independently from >NR 5 , —O—, —S—, or —(CH 2 )n- wherein n is 0 or 1;
  • R 5 in each occurrence is independently: 1) a substituted or an unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, any of which having up to 10 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or 2) hydrogen;
  • Y 1 or Y 2 is independently —(CH 2 )n-; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from: 1) alkyl, haloalkyl, —COR 9 , alkoxy, alkenyl, alkynyl, alkoxyalkyl, aryl, —CO 2 R 5 , —COR 5 , heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to 10 carbon atoms; or 2) hydrogen, halogen, cyano, or hydroxyl;
  • R 4 is selected independently from: 1) alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, alkylsufonyl, aryl, —CO 2 R 5 , —COR 5 , —NR 5 R 6 , —SO 2 NR 5 R 6 , heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to 10 carbon atoms; or 2) hydrogen, halogen, hydroxyl, or cyano;
  • any R 1 or R 2 are optionally substituted with at least one group independently selected from: 1) alkyl; alkoxy; alkylthio; haloalkyl; cycloalkyls; aryl; heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; haloalkoxy; —NR 8 2 ; —COR 9 ; —CONR 8 2 ; —SO 2 R 9 ; —NHSO 2 R 9 ; or —SO 2 NR 8 2 ; any of which having up to 10 carbon atoms; or 2) hydrogen, halogen, hydroxyl, cyano, or —OCH 2 O—;
  • R 8 in each occurrence, is independently: 1) an alkyl or a haloalkyl having up to 10 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently: 1) an alkyl or haloalkyl having up to 10 carbon atoms; or 2) hydrogen or hydroxyl;
  • any of R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, —COR 10 , —CO 2 R 10 , —CONR 10 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl or an aryl having up to 6 carbon atoms; or 2) hydrogen.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 and Y 2 are selected independently from >NR 5 , —O—, or —CH 2 —;
  • R 5 in each occurrence, is independently hydrogen or methyl
  • Y 1 or Y 2 is independently —CH 2 —
  • the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from an alkyl, a haloalkyl, an alkoxy, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to 10 carbon atoms;
  • R 4 is selected independently from: 1) an alkyl, a haloalkoxy, an aryl, or a heteroaryl or heterocyclyl having up to 10 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or 2) Y 1 R 1 ;
  • any of R 1 , R 2 , or R 5 is optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —NR 8 2 , —SO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) hydrogen, halogen, cyano, or —OCH 2 O—;
  • R 8 in each occurrence, is independently: 1) alkyl, haloalkyl, or aryl, any of which having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, or an aryl, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, —COR 10 , —CO 2 R 10 , —CONR 10 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl or an aryl having up to 6 carbon atoms; or 2) hydrogen.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof,
  • Y 1 and Y 2 are selected independently from >NR5 or —CH 2 —;
  • R 5 in each occurrence, is independently methyl or hydrogen
  • Y 1 or Y 2 is independently —CH 2 —; the corresponding R z , wherein z is 1 or 2, in each occurrence is independently selected from a substituted or an unsubstituted aryl, or a substituted or an unsubstituted heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; any of which having up to 10 carbon atoms;
  • any R 1 or R 2 are optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, —O—CH 2 —O—, —OCOR 9 , NR 8 2 , —SO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) hydrogen, halogen, or cyano;
  • R 8 and R 9 in each occurrence, are independently selected from: 1) an alkyl or an aryl having up to 10 carbon atoms; or 2) hydrogen; and
  • R 4 in each occurrence, is selected independently from a substituted or an unsubstituted: alkyl, aryl, or heteroaryl or heterocyclyl having up to 10 carbon atoms, wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO;
  • R 4 is optionally substituted with at least one group independently selected from: 1) an alkyl, a haloalkoxy, an alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl; and
  • R 10 in each occurrence, is selected independently from: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Still another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 is selected from >NR 5 , or —CH 2 —;
  • R 1 and R 2 are selected independently from a substituted or an unsubstituted cycloalkyl, aryl, or heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO or >SO 2 , any of which having up to 10 carbon atoms;
  • R 5 is selected from methyl or hydrogen
  • R 4 is selected from a substituted or an unsubstituted alkyl, aryl, or heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, any of which having up to 10 carbon atoms;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , -cyano, —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) alkyl, haloalkyl, or aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl; and
  • R 10 in each occurrence, is selected independently from: 1) alkyl, aryl, or heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Another aspect of the present invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 and R 2 are selected independently from a substituted or an unsubstituted aryl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO, any of which having up to 10 carbon atoms;
  • R 4 is selected from a substituted or an unsubstituted aryl, or a substituted or an unsubstituted heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, any of which having up to 10 carbon atoms;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, cyano, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or a heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) an alkyl, a haloalkoxy, an alkoxy, —COR 10 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl; and
  • R 10 in each occurrence, is selected independently from: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Still another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 , R 2 , and R 4 are selected independently from a substituted or an unsubstituted aryl, or a substituted or an unsubstituted heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O—, >N—, —S—, >SO 2 , or >CO, any of which having up to 10 carbon atoms;
  • R 1 , R 2 , and R 4 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —COR 10 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —SR 8 , —NHSO 2 R 9 , —SO 2 NR 8 2 , —SO 2 N 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, cyano, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or a heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 10 in each occurrence, is selected independently from: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 and R 2 are selected independently from: a) a substituted or an unsubstituted aryl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, any of which having up to 10 carbon atoms; b) hydrogen, or c) halogen or hydroxy;
  • R 4 is selected from a substituted or unsubstituted aryl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, any of which having up to 10 carbon atoms;
  • R 5 is an alkyl having up to 3 carbon atoms or hydrogen
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Yet another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 and R 2 are selected independently from: a) a substituted or an unsubstituted aryl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, any of which having up to 10 carbon atoms; b) hydrogen, or c) halogen or hydroxy;
  • R 4 is selected from: 1) a substituted or an unsubstituted alkyl or heterocyclyl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, any of which having up to 10 carbon atoms;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, cyano, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 and R 4 are selected independently from a substituted or an unsubstituted aryl or a substituted or an unsubstituted heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O—, >N—, or —S—, any of which having up to 10 carbon atoms;
  • R 11 in each occurrence, is selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • n is an integer from 0 to 3, inclusive;
  • R 1 and R 4 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl, any of which having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 4 is selected from a substituted or an unsubstituted heterocyclyl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, any of which having up to 10 carbon atoms;
  • n and m are independently an integer from 0 to 3, inclusive;
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —CO 2 R 8 , —SO 2 R 9 , —SR 8 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen;
  • R 4 is optionally substituted with at least one group independently selected from: 1) an alkyl, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , or —SO 2 NR 10 2 , any of which having up to 10 carbon atoms; or 2) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • R 4 can be selected from or
  • X is selected from CH 2 , O, NH, NMe, NEt, S, SO 2 , or CH(OH);
  • R 11 and R 12 in each occurrence, can be selected independently from OCF 3 , OMe, Cl, F, SO 2 Me, CF 3 , Me, COMe, SMe, CONHMe, NHSO 2 Me, SO 2 NH 2 , SO 2 NHMe, SO 2 NMe 2 , CONH 2 , CONMe 2 , CO 2 Me, CO 2 H, —OCH 2 O—, or OH.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 4 is selected from: 1) hydrogen, chloro, or hydroxy; or 2) a substituted or an unsubstituted aryl, heteroaryl, or alkoxy, any of which having up to 10 carbon atoms;
  • n and m are independently an integer from 0 to 3, inclusive;
  • R 11 and R 12 are selected independently from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently selected from: 1) an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen;
  • R 4 when R 4 is aryl or heteroaryl, R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 11 , R 12 , and R 13 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • n, and p are selected independently from an integer from 0 to 3, inclusive;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl, any of which having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Still another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 is selected from >NH or —O—;
  • R 1 is selected from a substituted or an unsubstituted alkyl, cycloalkyl, aryl, benzyl, or heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) —OCH 2 O—, halogen, or hydroxyl;
  • n and m are selected independently from an integer from 0 to 3, inclusive;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl, any of which having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen; and wherein
  • R 1 is optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, or a haloalkoxy, any of which having up to 10 carbon atoms; or 2) hydroxyl, CO 2 H, or CO 2 Et.
  • Another aspect of the present invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 is selected from >NR 5 or —(CH 2 )n- wherein n is 0;
  • R 5 is selected from methyl or hydrogen
  • R 1 and R 4 are selected independently from a substituted or an unsubstituted aryl, or a substituted or an unsubstituted heteroaryl or heterocyclyl comprising at least one heteroatom selected from —O—, >N—, —S—, >CO, or >SO 2 , any of which having up to 10 carbon atoms;
  • n is an integer from 0 to 3, inclusive;
  • R 11 in each occurrence, is selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 1 and R 4 are optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —SO 2 R 10 , —SR 8 , —NHSO 2 R 9 , —SO 2 NR 8 2 , or —SO 2 NR 10 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 10 in each occurrence, is independently selected from: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 2 is selected from >NR 5 or >(CH 2 )n wherein n is 0 or 1;
  • R 1 and R 2 are selected independently from: a) a substituted or an unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO or >SO 2 , any of which having up to 10 carbon atoms; b) hydrogen, or c) halogen or hydroxy;
  • R 5 is an alkyl having up to 3 carbon atoms or hydrogen
  • R 4 is selected from: 1) a substituted or an unsubstituted alkyl, aryl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, any of which having up to 10 carbon atoms; 2) hydrogen; or 3) halogen;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, cyano, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is a alkyl, an aryl, a heterocyclyl, or a heteroaryl
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Still another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 and R 2 are selected independently from: a) a substituted or an unsubstituted aryl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, any of which having up to 10 carbon atoms; b) hydrogen; or c) halogen or hydroxy;
  • R 4 is selected from: 1) a substituted or an unsubstituted alkyl, aryl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, any of which having up to 10 carbon atoms; 2) hydrogen; or 3) halogen;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is an alkyl, an aryl, a heterocyclyl, or a heteroaryl
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Yet another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 and R 2 are selected independently from: a) a substituted or an unsubstituted aryl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO or >SO 2 , any of which having up to 10 carbon atoms; b) hydrogen, or c) halogen or hydroxy;
  • R 4 is selected from a substituted or unsubstituted aryl or heteroaryl, any of which having up to 10 carbon atoms;
  • R 5 is an alkyl having up to 3 carbon atoms or hydrogen
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Another aspect of the present invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 1 and R 2 are selected independently from: 1) a substituted or an unsubstituted aryl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, any of which having up to 10 carbon atoms; or 2) hydrogen, halogen, or hydroxyl;
  • R 4 is selected from: 1) a substituted or an unsubstituted alkyl or heterocyclyl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, any of which having up to 10 carbon atoms;
  • R 1 and R 2 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Yet another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 4 is a substituted or an unsubstituted heterocyclyl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, and having up to 10 carbon atoms;
  • n and m are independently an integer from 0 to 3, inclusive;
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group selected independently from: 1) alkyl, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , any of which having up to 10 carbon atoms; or 2) hydroxyl; and
  • R 10 in each occurrence, is independently selected from: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 4 is selected from a substituted or an unsubstituted aryl, or a substituted or an unsubstituted heteroaryl or heterocyclyl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, or >CO, any of which having up to 10 carbon atoms;
  • R 11 in each occurrence, are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —CO 2 R 8 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • n is an integer from 0 to 3, inclusive;
  • R 12 is selected from OCF 3 , SMe, SO 2 Me, or SO 2 NHMe;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen;
  • R 4 is optionally substituted with at least one group selected independently from: 1) an alkyl, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , any of which having up to 10 carbon atoms; or 2) hydroxyl; and
  • R 10 in each occurrence, is independently selected from: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • R 4 can be selected from
  • X is selected from CH 2 , O, NH, NMe, NEt, S, SO 2 , or CH(OH);
  • R 11 in each occurrence, can be selected independently from OCF 3 , OMe, Cl, F, SO 2 Me, CF 3 , Me, COMe, CONHMe, NHSO 2 Me, SO 2 NH 2 , SO 2 NHMe, SO 2 NMe 2 , CONH 2 , CONMe 2 , CO 2 Me, CO 2 H, —OCH 2 O—, or OH.
  • Yet another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 4 is selected from: 1) a substituted or unsubstituted alkoxy, aryl, or heteroaryl comprising at least one heteroatom selected from —O—, —S—, >N—, or >NH, any of which having up to 10 carbon atoms; 2) hydrogen; or 3) chloro or hydroxyl;
  • n and m are independently an integer from 0 to 3, inclusive;
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) alkyl, haloalkoxy, alkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or —NR 10 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 11 and R 13 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • n and p are selected independently from an integer from 0 to 3, inclusive;
  • R 12 is selected from OCF 3 , SMe, SO 2 Me, or SO 2 NHMe;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl, any of which having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is independently selected from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms.
  • Still another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 4 is selected from
  • X is selected from CH 2 , O, NH, NMe, NEt, S, SO 2 , or CH(OH);
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • n and m are selected independently from an integer from 0 to 3, inclusive;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl, any of which having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is independently selected from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms.
  • Yet another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 4 is selected from: 1) a substituted or an unsubstituted alkoxy, aryl, or heteroaryl comprising at least one heteroatom selected from —O—, >N—, or —S—, any of which having up to 10 carbon atoms; or 2) hydrogen, chloro, or hydroxyl;
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • n and m are selected independently from an integer from 0 to 3, inclusive;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl, any of which having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is independently selected from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 4 is optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkoxy, —COR 10 , —CONR 8 2 , —SO 2 R 10 , —SO 2 NR 10 2 , or NR 10 8 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl; and
  • R 10 in each occurrence, is independently selected from: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • Y 1 is selected independently from >NRW or —(CH 2 )n- wherein n is 0 or 1;
  • R 1 and R 4 are selected independently from: 1) a substituted or an unsubstituted alkyl, cycloalkyl, aryl, or heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO, or >SO 2 , any of which having up to 10 carbon atoms; or 2) hydrogen, halogen, or hydroxyl;
  • R 5 is selected from an alkyl having up to 3 carbon atoms or hydrogen
  • R 2 is selected from a heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO, or >SO 2 , any of which having up to 10 carbon atoms;
  • R 1 and R 4 are optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, cyano, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl, any of which having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is independently selected from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 2 is selected from a heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO or >SO 2 , having up to 10 carbon atoms;
  • R 4 is selected from: 1) a substituted or an unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO or >SO 2 , any of which having up to 10 carbon atoms; or 2) hydrogen, halogen; or hydroxyl;
  • n is an integer from 0 to 3, inclusive;
  • R 12 in each occurrence, is selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 4 is optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, cyano, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 2 is selected from a substituted or an unsubstituted heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO, or >SO 2 , any of which having up to 10 carbon atoms;
  • n and m are independently an integer from 0 to 3, inclusive;
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl, having up to 6 carbon atoms; or 2) hydrogen;
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms;
  • R 2 is optionally substituted with at least one group independently selected from: 1) alkyl, —COR 10 , —CONR 8 2 , —SO 2 R 10 , or —SO 2 NR 10 2 , any of which having up to 10 carbon atoms; or 2) hydroxyl; and
  • R 10 in each occurrence, is independently: 1) an alkyl, an aryl, or a heterocyclyl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms; or 2) hydrogen.
  • Another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 2 is selected from a heterocyclyl or a heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO, or >SO 2 , any of which having up to 10 carbon atoms;
  • n and m are independently an integer from 0 to 3, inclusive;
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms.
  • R 2 can be selected from
  • Another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • a salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
  • R 2 is selected from a substituted or an unsubstituted heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >CO, or >SO 2 , any of which having up to 10 carbon atoms;
  • R 2 is optionally substituted with at least one group independently selected from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —COR 10 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —SR 8 , —NHSO 2 R 9 , —SO 2 NR 8 2 , —SO 2 NR 02 , or —NR 10 2 , any of which having up to 10 carbon atoms; or 2) halogen, oxo, hydroxyl, cyano, or —OCH 2 O—;
  • n and m are independently an integer from 0 to 3, inclusive;
  • R 11 and R 12 are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, —COR 9 , —CO 2 R 8 , —CONR 8 2 , —SO 2 R 9 , —NHSO 2 R 9 , or —SO 2 NR 8 2 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or —OCH 2 O—;
  • R 8 in each occurrence, is selected independently from: 1) an alkyl, a haloalkyl, or an aryl having up to 6 carbon atoms; or 2) hydrogen; and
  • R 9 in each occurrence, is selected independently from an alkyl, a haloalkyl, an aryl, or a heterocyclyl or heteroaryl comprising at least one heteroatom selected from —O— or >N—, any of which having up to 10 carbon atoms.
  • One aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the following formula:
  • C is not CH 3 , CH 2 OCH 3 ,
  • C is CH 3 , CH 2 OCH 3 , or
  • C is not OH, NH 2 ,
  • halogen or ‘halo’ includes fluorine, chlorine, bromine, or iodine.
  • alkyl group is used to refer to both linear or branched alkyl groups.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, and the like.
  • an alkyl group has from 1 to 10 carbon atoms.
  • all structural isomers of a given structure for example, all enantiomers and all diasteriomers, are included within this definition.
  • propyl is meant to include n-propyl and iso-propyl
  • butyl is meant to include n-butyl, iso-butyl, t-butyl, sec-butyl, and so forth.
  • Haloalkyl is a group containing at least one halogen and an alkyl portion as define above. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. Exemplary haloalkyl groups include fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, trifluoromethyl, and the like. Unless otherwise specified, a haloalkyl group has from 1 to 10 carbon atoms.
  • acyl is used to refer to an H—CO— or an alkyl-CO— group, where alkyl is defined herein.
  • exemplary acyl groups include, but are not limited to, acetyl, propionyl, iso-propionyl, tert-butionyl, and the like.
  • Cycloalkyl group refers to a cyclic alkyl group which may be mono or polycyclic.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
  • a cycloalkyl group has from 3 to 10 carbon atoms.
  • Alkoxy refers to an —O(alkyl) group, where alkyl is as defined above. Therefore, unless otherwise specified, all isomers of a given structure are included within a definition. Exemplary alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, and the like. Unless otherwise specified, an alkoxy group has from 1 to 10 carbon atoms.
  • Alkoxyalkyl is an alkyl group with an alkoxy substituent, where alkoxy and alkyl groups are as defined above.
  • exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, isopropoxymethyl isopropoxyethyl, isopropoxypropyl, t-butoxymethyl, t-butoxymethyl, t-butoxypropyl, and the like.
  • an alkoxyalkyl group typically has from 1 to 10 carbon atoms.
  • Haloalkoxy is an alkoxy group with a halo substituent, where alkoxy and halo groups are as defined above.
  • exemplary haloalkoxy groups include chloromethoxy, trichloroethoxy, trifloroethoxy, perfluoroethoxy (—OCF 2 CF 3 ), trifluoro-t-butoxy, hexafluoro-t-butoxy, perfluoro-t-butoxy (—OC(CF 3 ) 3 ), and the like.
  • an haloalkoxy group typically has from 1 to 10 carbon atoms.
  • Alkylthio refers to an —S(alkyl) goup, where alkyl group is as defined above.
  • alkyl groups include methylthio, ethylthio, propylthio, butylthio, iso-propylthio, iso-butylthio, and the like. Unless otherwise specified, an alkylthio group typically has from 1 to 10 carbon atoms.
  • Alkylsulfonyl refers to a —SO 2 (alkyl) group, where alkyl group is as defined above.
  • alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, and the like. Unless otherwise specified, an alkylsulfonyl group typically has from 1 to 10 carbon atoms.
  • Alkenyl is an unsaturated aliphatic group containing a C ⁇ C double bond.
  • alkenyl groups include ethenyl, propenyl, prop-1-enyl, isopropenyl, butenyl, but-1-enyl, isobutenyl, pentenyl, pent-1-enyl, hexenyl, pent-2-enyl, 2-methyl-but-2-ene, 2-methyl-pent-2-enyl, and the like.
  • an alkenyl group typically has from 2 to 10 carbon atoms.
  • Alkynyl is an unsaturated aliphatic group containing a C ⁇ C triple bond.
  • exemplary alkynyl groups include ethenyl, propynyl, prop-1-ynyl, butynyl, butaynyl, and the like. Unless otherwise specified, an alkynyl group typically has from 2 to 10 carbon atoms.
  • Aryl is optionally substituted monocylic or polycyclic aromatic ring system of 6 to 14 carbon atoms.
  • exemplary groups include phenyl, naphthyl, and the like. Unless otherwise specified, an aryl group typically has from 6 to 14 carbon atoms.
  • Aralkyl is an alkyl group with an aryl substituent, where alkyl and aryl groups are as defined above.
  • exemplary aralkyl groups include, but are not limited to, benzyl, phenethyl (for example, 2-phenethyl), phenylpropyl (for example, 3-phenylpropyl), naphthylmethyl (for example, 1-naphthylmethyl and 2-naphthylmethyl), and the like.
  • Heteroaryl is an aromatic monocyclic or polycyclic ring system of 4 to 10 carbon atoms, having at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >NH or NR, and the like, wherein R is a substituted or unstubstituted alkyl, aryl, or acyl, as defined herein.
  • >NH or NR are considered to be included when the heteroatom or heterogroup can be >N—.
  • heteroaryl groups include pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furanyl, indolyl, isoindolyl, benzo[1,3]dioxolyl, 1,3-benzoxathiole, quinazolinyl, pyridyl, thiophenyl, and the like.
  • a heteroaryl group typically has from 4 to 10 carbon atoms.
  • the heteroaryl group can be bonded to the pyrimidine core structure at a ring carbon atom, or, if applicable for a N-substituted heteroaryl such as pyrrole, can be bonded to the pyrimidine core structure through the heteroatom that is formally deprotonated to form a direct heteroatom-pyrimdine ring bond.
  • Heterocyclyl is a non-aromatic saturated monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO.
  • exemplary heterocyclyl groups include aziridinyl, pyrrolidinyl, piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, and the like.
  • a heterocyclyl group typically has from 2 to 10 carbon atoms.
  • a heterocyclyl group can be bonded through a heteroatom that is formally deprotonated or a heterocyclyl group can be bonded through a carbon atom of the heterocyclyl group.
  • Carboxylic acid or its derivatives may be amides or esters.
  • Exemplary carboxylic acid groups include CONH 2 , CONHMe, CONMe 2 , CONHEt, CONEt 2 , CONHPh, COOH, COOCH 3 , COOC 2 H 5 , or COOC 3 H 7 .
  • Cyclic amines means nitrogen containing heteroaryl or heterocyclyl groups.
  • A is selected from —NH 2 , —SEt, —OH,
  • B is selected from —OH, —OEt, —NHMe, —NH-i-Pr, —O-i-Pr,
  • C is selected from —Cl, —OH, —CH 3 ,
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof.
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture wherein:
  • A3 is H, Cl, NH 2 , SH, SMe, SEt, or OH;
  • n 0 or 1
  • m 5, 6, 7, or 8;
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
  • A3 is H, Cl, NH 2 , SH, SMe, SEt, or OH;
  • n 0 or 1
  • m 5, 6, 7, or 8;
  • X 2 is H, F, OCH 3 , OCH 2 CH 3 , SCH 3 , CH 3 , CF 3 , OCF 3 , or SO 2 CH 3 .
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
  • A is selected from
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
  • a and B are selected independently from
  • Another aspect of this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
  • A is selected from —H, —Cl, —NH 2 , —SH, —SEt, —OH,
  • B and C are independently selected from —Cl, —OH, —OEt, —NHMe, —NH-i-Pr, —O-i-Pr, Pr, —CH 3 ,
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
  • a and B are selected independently from
  • this invention provides compounds, and compositions comprising the compounds, wherein the compounds have the formula:
  • a pharmaceutically acceptable or a non-pharmaceutically acceptable salt including a pharmaceutically acceptable or a non-pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
  • a and B are selected independently from
  • this invention provides substituted pyrimidine compounds, wherein the compound can be: 1-(2,6-Diphenyl-pyrimidin-4-yl)-piperidin-4-ol; 1-[2-(4-Methanesulfonyl-phenylamino)-6-phenyl-pyrimidin-4-yl]-piperidin-4-ol; 1-[4-(4-Methanesulfonyl-phenylamino)-6-phenyl-pyrimidin-2-yl]-piperidin-4-ol; (6-Morpholin-4-yl-2-phenyl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine; (4-Morpholin-4-yl-6-phenyl-pyrimidin-2-yl)-(4-trifluoromethoxy-phenyl)-amine; 4-[4-(4-Hydroxy-piperidin-1-yl)-6-phenyl-pyrimidin-4
  • substituents Y 1 , R 1 , Y 2 , R 2 , R 3 and R 4 can be selected according to the following listings, wherein each substituent is defined in Table 1.
  • the substituent Y 1 and Y 2 can be selected independently from Y A , Y B , Y C , Y D , Y E , Y F , Y G , Y H , Y I , or Y J .
  • the substituent R 1 can be selected independently from R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 1G1 , R 1G2 , R 1G3 , R 1G4 , R 1G5 , R 1H1 , R 1H2 , R 1H3 , R 1H4 , R 1H5 , R 1I , R 1J , R 1K , R 1L , R 1M , R 1N , R 1O , R 1P , or R 1Q .
  • the substituent R 2 can be selected independently from R 2A , R 2B , R 2C , R 2D , R 2E , R 2F , R 2G1 , R 2G2 , R 2G3 , R 2G4 , R 2G5 , R 2H1 , R 2H2 , R 2H3 , R 2H4 , R 2H5 , R 2I , R 2J , R 2K , R 2L , R 2M , R 2N , R 2O , R 2P , or R 2Q .
  • the moieties Y 1 R 1 and Y 2 R 2 can be selected independently from YR A , YR B , YR C , YR D , YR E , YR F , YR G , YR H , YR I , YR J , or YR K , as defined herein.
  • the substituent R 3 can be selected independently from R 3A , R 3B , R 3C , R 3D , R 3E , R 3F , R 3G , R 3H , R 3I , R 3J , R 3K , R 3L , R 3M , R 3N , R 3O , R 3P1 , R 3P2 , R 3P3 , R 3P4 , R 3P5 , R 3Q1 , R 3Q2 , R 3Q3 , R 3Q4 , R 3Q5 , R 3R , R 3S , R 3T , R 3U , or R 3V .
  • the substituent R 4 can be selected independently from R 4A , R 4B , R 4C , R 4D , R 4E , R 4F , R 4G , R 4H , R 4I , R 4J , R 4K , R 4L , R 4M , R 4N , R 4O , R 4P1 , R 4P2 , R 4P3 , R 4P4 , R 4P5 , R 4Q1 , R 4Q2 , R 4Q3 , R 4Q4 , R 4Q5 , R 4R , R 4S , R 4T , R 4U , or R 4V .
  • Y A >NR 5 , wherein R 5 is selected from R 5A through R 5G Y B —(CH 2 )n—, n is 0 to 3 Y C —(CH 2 )p(CH ⁇ CH)(CH 2 )q—, p and q are independently 0 to 3 Y D >CR 5 R 6 , wherein R 5 is selected from R 5A through R 5G , and R 6 is selected from R 6A through R 6G Y E —(CH 2 )p(C ⁇ C)(CH 2 )q—, p and q are independently 0 to 3 Y F —O— Y G >CO Y H —S— Y I >SO Y J >SO 2 YR A saturated or unsaturated carbocyclic or N-heterocyclic ring having up to 10 carbon atoms YR B saturated or unsaturated carbocyclic or N-heterocyclic ring having up to 10 carbon atom
  • the number of carbon atoms on the substituents refers to the carbon atoms on the base chemical moiety, and does not include the carbon atoms in any optional substituent. Again, unless otherwise indicated, any substituents are limited in size by the carbon atoms listed in the definitions of the substitutents.
  • Any carbocyclic ring, N-heterocyclic ring, morpholinyl, piperazinyl, thiomorpholinyl, pyrrolidinyl, or piperidinyl can be optionally substituted with at least one hydroxyl, halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, aryl, or heteroaryl any of which having up to 6 carbon atoms.
  • the piperazine nitrogen is optionally substituted by an alkyl, a cycloalkyl, an acyl, a haloalkyl, an alkoxyalkyl, SO 2 R 7 , SO 2 NR 7 2 , or CO 2 R 7 , wherein R 7 is independently selected from: a) an alkyl or an aryl having up to 8 carbon atoms; or b) hydrogen.
  • R 1 , R 2 , R 5 , or R 6 moieties that do not constitute hydrogen, halogen, cyano, or hydroxyl can be optionally substituted with at least one group independently selected from: 1) alkyl; alkoxy; alkylthio; haloalkyl; cycloalkyls; aryl; heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 or >CO; haloalkoxy; —OCH 2 O—; —OCOR 9 ; N(R 8 ) 2 ; —COR 9 ; —CON
  • R 8 in each occurrence, is independently: 1) an alkyl; a haloalkyl; a heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; or an aryl having up to 6 carbon atoms; or 2) hydrogen.
  • R 9 in each occurrence, is independently an alkyl; a haloalkyl; an aryl; or a heterocyclyl or heteroaryl comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >SO 2 , or >CO; having up to 8 carbon atoms; wherein R 9 is optionally substituted with: 1) an alkyl, an alkoxy, a carboxylic acid, or a carboxylic acid ester, any of which having up to 8 carbon atoms; 2) halogen; or 3) hydroxyl.
  • R 3 or R 4 moieties that do not constitute hydrogen, halogen, cyano, or hydroxyl can be optionally substituted with at least one group independently selected from: 1) alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, —COR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , or —N(R 10 ) 2 , any of which having up to 10 carbon atoms; 2) halogen; or 3) hydroxyl; wherein R 10 , in each occurrence, is independently: 1) an alkyl or an aryl having up to 6 carbon atoms; or 2) hydrogen.
  • compounds provided herein may be chiral or achiral, or they may exist as racemic mixtures, diastereomers, pure enantiomers, a prodrug, a tautomer or any mixture thereof.
  • chiral compounds separate enantiomers, separate diastereomers, and any mixture of enantiomers, diastereomers, or both are encompassed herein.
  • the present invention also encompasses any combination of compounds provided herein, including any salts, including pharmaceutically acceptable and non-pharmaceutically acceptable salts, or any mixture thereof.
  • pharmacologically acceptable salt or “pharmacologically acceptable” salt refers generally to a salt or complex of the compound or compounds in which the compound can be either anionic or cationic, and have associated with it a counter cation or anion, respectively, that is generally considered suitable for human or animal consumption.
  • a pharmaceutically acceptable salt can refer to a salt of a compound disclosed herein that forms upon reaction or complexation with an acid whose anion is generally considered suitable for human or animal consumption.
  • pharmacologically acceptable salts include salts with organic acids or inorganic acids.
  • pharmacologically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, propionate, lactate, maleate, malate, succinate, tartarate, and the like.
  • Salts may also be formed by deprotonating acid moiety of compound, such as a carboxylic acid moiety, OH, or NH, and the like, using a base such as an organic base, an inorganic base, an organometallic base, a Lewis base, a Br ⁇ nsted base, or any mixture thereof.
  • suitable pharmaceutically acceptable salts can include alkali metal salts, alkaline earth metal salts, or salts with organic basis, and the like.
  • alkali metal salts include, but are not limited to, sodium and potassium salts
  • examples of salts with organic basis include, but are not limited to, meglumine salts, and the like.
  • the pharmacologically acceptable salts may be prepared by conventional means. Additional examples of pharmaceutically acceptable salts, and methods of preparing such salts, are found, for example, in Berg et.al., J. Pharma. Sci, 66, 1-19 (1977).
  • this invention also provides a composition comprising at least one compound as disclosed herein, including a composition comprising a pharmaceutically acceptable carrier and at least one compound as disclosed herein.
  • the at least one compound can be present as a neutral compound, as a salt, or as any combination thereof.
  • This invention also encompasses a composition comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof.
  • this invention encompasses a pharmaceutical composition, comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, or a transdermal patch.
  • a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof, wherein the pharmaceutical composition is in the form of a tablet, a capsule,
  • this invention encompasses a pharmaceutical composition, comprising at least one compound as disclosed herein, and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof; and further comprising an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, an anti-inflammatory agent, an antirheumatic agent, a cardiovascular agent, or any combination thereof.
  • a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof
  • Another aspect of this invention is directed to using the compounds and compositions disclosed herein in a method of treating a condition or disease state mediated by the low expression of Perlecan, comprising administering an amount of at least one compound as disclosed herein, effective to induce Perlecan expression.
  • a further aspect of this invention is directed to using the compounds and compositions disclosed herein in a method of treating atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia, comprising administering an effective amount of at least one compound as disclosed herein.
  • One more aspect of the present invention provides a process for the preparation of the compounds of the general formula types disclosed herein.
  • substituted pyrimidine analogs may be prepared generally using standard synthetic methods and employing starting materials that are readily available commercially.
  • the general synthetic methods provided will ve readily understood by one of ordinary skill in the art, and any variations needed for a particular species are simple and readily understood and appreciated by the skilled artisan.
  • variable chemical moieties refer to any chemical group consistent with the description of the compound and substituents on that compound as provided herein.
  • palladium catalyst refers to a suitable palladium catalyst, typically a complex of Pd(0) or Pd(II), including but not limited to, such compounds as palladium(0) tetrakis(triphenylphosphine), tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, that is known to catalyze the reaction shown.
  • the catalytic system may also include monodentate or chelating ligands, examples of which include, but are not limited to, 2,2′-bis(diphenyl phosphino)-1,1-binapthyl, tri-tert-butyl phosphine, and the like, and may also include a base such as sodium carbonate, sodium or potassium tert-butoxide, or potassium phosphate.
  • monodentate or chelating ligands examples of which include, but are not limited to, 2,2′-bis(diphenyl phosphino)-1,1-binapthyl, tri-tert-butyl phosphine, and the like, and may also include a base such as sodium carbonate, sodium or potassium tert-butoxide, or potassium phosphate.
  • Transition metal catalyzed reactions may be typically carried out at ambient temperature or at elevated temperatures using various inert solvents, examples of which include, but are not limited to, toluene, dioxane, DMF, n-methyl pyrrolidine, ethylene glycol, dimethyl ether, diglyme, acetonitrile, or any combination thereof.
  • commonly employed reagent and catalyst pairs include, but are not limited to, aryl boronic acids and palladium(0) (Suzuki reaction, Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457).
  • Halogenation was carried out by using reagent chosen from phosphorus oxychloride (POCl 3 ), thionyl chloride (SOCl 2 ) and the like at a temperature in the range of about 80° C. to about 120° C., for about 4 to about 8 hours, followed by pH adjustment of resultant mixture to about 6 to about 7.
  • reagent chosen from phosphorus oxychloride (POCl 3 ), thionyl chloride (SOCl 2 ) and the like at a temperature in the range of about 80° C. to about 120° C., for about 4 to about 8 hours, followed by pH adjustment of resultant mixture to about 6 to about 7.
  • Amination was carried out by using amines in presence of a solvent chosen from acetone, acetonitrile, dimethylformamide, dimethylacetamide and the like, with or with out base selected from triethylamine, N,N-diisopropyl ethyl amine, potassium carbonate, sodium carbonate, sodium hydride.
  • the reaction temperature was about 20° C. to about 120° C.
  • the duration of the reaction was in the range of about 4 to about 20 hours.
  • Arylation was carried out by aryl boronic acids for example in the presence of a palladium catalyst and a base such as sodium carbonate, potassium carbonate, sodium or potassium tert-butoxide, potassium phosphate and the like, at ambient temperature or elevated temperatures using various inert solvent including but not limited to toluene, dioxane, DMF, n-methyl pyrolidine, ethylene glycol, dimethyl ether, diglyne, and acetonitrile.
  • a palladium catalyst and a base such as sodium carbonate, potassium carbonate, sodium or potassium tert-butoxide, potassium phosphate and the like
  • palladium catalysts include [tetrakis-(triphenylphosphine)palladium (0)] [(PPh 3 ) 4 Pd], tris(dibenzeledine acetone)dipalladium (0) or palladium (II) acetate[Pd(OAc) 2 ], [bis(triphenylphosphine)palladium(II)chloride] [(PPh 3 ) 2 PdCl 2 ] (Suzuki reaction, Miyaura and Suzuki (1995, Chemical Reviews 95:2457).
  • any compound of any formula disclosed herein may be obtained using procedures provided in the following reaction Schemes, as well as in the schemes provided in the Examples and the Examples themselves, by selecting suitable starting materials and following analogous procedures.
  • any compound of any formula disclosed above, and exemplified herein may be obtained by using the appropriate starting materials and appropriate reagents, with the desired substitutions, and following procedures analogous to those described herein.
  • compounds of this invention can be prepared as follows.
  • the present invention also provides a process of preparing compounds of the present invention, examples of which are also illustrated in Scheme B, by selecting the proper reagents to be used in the syntheses provided therein, and by employing a combination of the following steps.
  • Y 1 and Y 2 can be selected independently from NH or —(CH 2 )n- wherein n is typically 0, although n can be 1 or 0; Y 1 —R 1 and Y 2 —R 2 can be selected independently from N-containing cyclic amines; and R 4 can be selected independently from Y 1 —R 1 , wherein Y 1 , R 1 , Y 2 , and R 2 are defined herein.
  • Table 3 provides a listing of exemplary generic pyrimidine compounds types encompassed by the present invention, based upon the general structure shown with substitutents A, B, and C.
  • a synthetic Scheme or Example is provided that details at least one synthetic method that can be used to prepare any compound that is encompassed by that generic compound type.
  • any compound encompassed by the present invention can be prepared.
  • SR (R aryl, NHAryl 1 Aryl 2 E24 CH 2 CO 2 R) 23.
  • SR (R alkyl, Cl Aryl E24 CH 2 CO 2 R) 24.
  • SR (R alkyl, OH Aryl E24 CH 2 CO 2 R) 25.
  • NHR (R alkyl, Aryl S3 cycloalkyl, benzyl) 29. OH OH Aryl S5 30.
  • NHR (R NHAryl 1 Aryl 2 E133 alkyl, cycloalkyl) 31.
  • NHR (R Cl Aryl E132 alkyl, cycloalkyl) 32.
  • N-heterocycle NRAryl 1 (R H, Me) Aryl 2 S5 33.
  • N-heterocycle Cl Aryl S5 35.
  • Aryl 1 NHAryl 2 N-heterocycle S10 38. Aryl 1 NHAryl 2 Aryl 3 E122 39. Aryl 1 Cl Cl E113 40. Aryl 1 N-heterocycle Cl S9 41. Aryl 1 OH OH E113 42. Aryl 1 Cl NHAryl 2 S10 43. Aryl 1 OH Aryl 2 E121 44. Aryl 1 Cl Aryl 2 E121 45. H NHAryl 1 Aryl 2 E118 46. H OH Aryl E118 47. H Cl Aryl E118 48. Cl Cl Aryl S5 49. Cl NHR (R alkyl, Aryl S3 cycloalkyl, benzyl) 50. Cl N-heterocycle Aryl S5 51. Cl Cl NHAryl E119 Prodrugs
  • prodrugs comprise functional derivatives of the claimed compounds which are capable of being enzymatically activated or converted into the more active parent form.
  • administering encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Wihnan, 14 Biochem. Soc. Trans. 375-82 (1986); Stella et al., Prodrugs: A Chemical Approach to Targeted Drug Delivery in Directed Drug Delivery 247-67 (1985).
  • the prodrugs of present invention include, but are not limited to derivatives of carboxylic acid, sulfonamide, amine, hydroxyl, and the like, including other functional groups and including any combination thereof.
  • this invention provides a pharmaceutical composition, comprising one or more compounds of any formula in any combination described above and optionally comprising a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof.
  • this invention affords a method of treating a condition or disease state mediated by the low expression of Perlecan, comprising administering at least one compound as disclosed herein, in an amount effective to induce Perlecan expression.
  • this invention also provides a method of treating atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia, comprising administering an effective amount of at least one compound as disclosed herein.
  • One aspect of the present invention comprises methods and compositions comprising the compounds of the present invention for the treatment and prevention of conditions or diseases that have as an aspect of the disease or condition, unwanted cellular proliferation occurring or are the result of cellular proliferation.
  • vascular diseases such as cardiovascular diseases, organ transplant sequellae, vascular occlusive conditions including, but not limited to, neointimal hyperplasia, restenosis, transplant vasculopathy, cardiac allograft vasculopathy, atherosclerosis, and arteriosclerosis, are caused by or have collateral damage due to unwanted cellular proliferation.
  • One aspect of the present invention relates to methods and compositions for the treatment and prevention of SMC proliferation, preferably comprising compositions and compounds having cellular antiproliferative activity. These compounds as described herein and compositions comprising such compounds are referred to as antiproliferative compounds or compositions. At least one activity of one or more of these compounds is that the compound has the activity of affecting the synthesis of proteoglycans including induction and synthesis of proteoglycans and active fragments of proteoglycans. Thus, one aspect of the activity of one or more of the compounds and compositions of the present invention comprise molecules that induce HSPG production and that regulate SMC proliferation.
  • 2-(3-Chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-4-ol 25.
  • 2-(2-Amino-6-phenyl-pyrimidin-4-ylamino)-benzoic acid 27.
  • 4,6-Bis-(4-fluoro-phenyl)-pyrimidin-2-ylamine 43.
  • [4-(3-Chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-2-ylamino]- acetic acid ethyl ester 45.
  • assays that can be used to determine the activity of the compounds of the present invention include other methods for measuring the induction of perlecan synthesis. For example, in one assay, perlecan is induced in cells by certain inducers, and the response is measured. Compounds of the present invention are then added to a replicate assay and the effect on perlecan induction is determined. Using such methods, compounds are determined that can either inhibit perlecan, elevate induction of perlecan, or that have no effect at all. Those compounds that are effective as therapeutic agents can then be used in animals, humans or patients with cellular proliferation disease aspects, such as vascular-associated diseases or SMC (smooth muscle cell) proliferation pathologies.
  • SMC smooth muscle cell proliferation pathologies.
  • Another assay for determining compounds having SMC effects comprises adding a composition suspected of effecting SMC proliferation to smooth muscle cells in growth medium or serum-free medium.
  • the change in cell proliferation can be measured by methods known to those skilled in the art, such as incorporation of labeled nucleotides into dividing cells' DNA, and compared to the proliferation of cells which are not treated with the compound.
  • Other measurements include directly determining levels of HSPG synthesis by measuring the amount or change in amount of HSPG such as with ELISA for HSPGs, and compared to the amount of HSPG synthesis in untreated cells.
  • Other indirect or direct measurements are contemplated by the present invention and are known to those skilled in the art.
  • such methods include, but are not limited to, measurement of RNA levels, RT-PCR, Northern blotting, Western blotting promoter-based assays to identify compounds that affect one or more proteoglycans and assays for proteoglycan biological activity shown by recombinant proteins, partially purified proteins, or lysates from cells expressing proteoglycans in the presence or absence of compounds of interest.
  • An assay for identifying and determining an activity of one or more of the compounds of the present invention comprises identifying compounds that interact with the promoter regions of a gene, or interact and affect proteins that interact with the promoter region, and are important in the transcriptional regulation of the protein's expression.
  • the method comprises a vector comprising regulatory sequences of the perlecan gene and an indicator region controlled by the regulatory sequences, such as an enzyme, in a promoter-reporter construct.
  • the protein product of the indicator region is referred to herein as a reporter enzyme or reporter protein.
  • the regulatory region of the sequence of perlecan comprises a range of nucleotides from approximately ⁇ 4000 to +2000 wherein the transcription initiation site is +1, more preferably, from ⁇ 2500 to +1200, most preferably, from ⁇ 1500 to +800 relative to the transcription initiation site.
  • Cells are transfected with a vector comprising the promoter-reporter construct and then treated with one or more compositions comprising at least one compound of the present invention.
  • the transfected cells are treated with a composition comprising a compound suspected of affecting the transcription of perlecan and the level of activity of the perlecan regulatory sequences are compared to the level of activity in cells that were not treated with the compound.
  • the levels of activity of the perlecan regulatory sequences are determined by measuring the amount of the reporter protein or determining the activity of the reporter enzyme controlled by the regulatory sequences.
  • An increase in the amount of the reporter protein or the reporter enzyme activity shows a stimulatory effect on perlecan, by positively effecting the promoter, whereas a decrease in the amount or the reporter protein or the reporter enzyme activity shows a negative effect on the promoter and thus, on perlecan.
  • the present invention comprises methods and compositions that can be used with gene therapy methods and composition, such as those gene therapy methods comprising administering compositions comprising nucleic acids that affect the synthesis or expression of HSPGs, particularly perlecan.
  • gene therapy methods and composition such as those gene therapy methods comprising administering compositions comprising nucleic acids that affect the synthesis or expression of HSPGs, particularly perlecan.
  • Such methods and compositions are taught in U.S. patent application Ser. No. 10/091,357, incorporated herein by reference.
  • the present invention comprises methods and compositions for mediating proteoglycan synthesis, expression and for the maintenance of SMC in a quiescent state.
  • Methods and compositions of the present invention comprise treatment and prevention of vascular diseases and pathologies related to cellular proliferation, such as SMC proliferation.
  • Such methods and compositions comprise methods for inhibition of SMC growth and proliferation, and for induction of quiescence in smooth muscle cells.
  • aspects of the present invention comprise methods and compositions for inducing proteoglycan synthesis, particularly HSPG synthesis and expression including, but not limited to, the induction of HSPGs such as syndecans, glypicans, and perlecans, and preferably perlecan synthesis and gene expression.
  • HSPG HSPG synthesis and expression
  • Perlecan is a major extracellular HSPG in the blood vessel matrix. It interacts with extracellular matrix proteins, growth factors, and receptors. Perlecan is also present in basement membranes other than blood vessels and in other extracellular matrix structures.
  • the activities of the compounds included in the present invention affect cells or tissues to increase the synthesis of proteoglycans by those cells or tissues or may act directly upon one or more proteoglycans to modulate the biological activity or to increase the biological stability of the proteoglycan itself, for example, of the protein perlecan. Activities also included herein are ones that increase the biosynthesis of one or more proteoglycans by increasing the transcription of the poteoglycan gene, increasing the biological stability, of the proteoglycan mRNA or increasing the translation of proteoglycan mRNA into protein. Further activites include activities of compounds that can block or decrease the effects of agents or proteins that inhibit the activity of proteoglycans.
  • the present invention comprises methods and compositions for the treatment and prevention of smooth muscle cell proliferation, including vascular occlusive pathologies.
  • Such methods comprise administration of compositions comprising compounds capable of inhibiting SMC proliferation, such as compositions comprising compounds disclosed herein that inhibit SMC proliferation.
  • Administration of such compounds that are effective in inhibiting SMC proliferation are administered to humans and animals suspected of having or who have, for example, vasculopathy or who have undergone angioplasty or other procedures damaging to the endothelium.
  • Effective amounts are administered to such humans and animals in dosages that are safe and effective, including, but not limited to, the ranges taught herein.
  • Routes of administration include, but are not limited to, those disclosed herein.
  • compositions comprising such compounds may be used in conjunction with other therapeutic agents or in methods comprising steps such as altered patient activities, including, but not limited to, changes in exercise or diet.
  • the present invention also comprises methods and compositions comprising compounds described herein that have an activity associated with modulation of glycosidase enzymes and thus, affecting the substrates for such enzymes.
  • Glycosidase enzymes and their activity with their substrates are aspects of a variety of diseases such as vascular conditions, including those conditions discussed supra, proteoglycan-associated diseases, supra, associated diseases with vascular components, including but not limited to, kidney disease, ischemic heart disease, cardiovascular disease, generalized vascular disease, proliferative retinopathy, macroangeopathy, inflammatory diseases and metastatic diseases such as cancer, cellular proliferative conditions, and solid and blood borne tumors or other oncological conditions.
  • Compounds described herein that have an activity that affects the concentrations of substrates of glycosidase enzymes are used in methods of treatment of such vascular, inflammatory, metastatic and systemic diseases.
  • Compounds or compositions comprising such compounds that are effective in modulating glycosidase enzyme activity are useful in treating and/or preventing cancer including, but not limited to, malignant and non-malignant cell growth, and the like.
  • the compounds disclosed herein are useful in modulating heparanase activity or the activity of other glycosidases as a means for treating and preventing autoimmune diseases.
  • the inhibition of heparanase or the activity of other glycosidases using the compounds of the present invention finds utitlity in treating arthritis and other autoimmune diseases. More specifically, the compounds of the present invention are useful in the treatment or prophylaxis of at least one autoimmune-related disease in a cell, tissue, organ, animal, or patient including, but not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/ admireer's granulomatosis, sarcoidosis, orchit
  • Compounds having heparanase activity inhibition that are effective for example, in treatment of cancer and autoimmune disease, can be determined using assays such as those disclosed in U.S. patent application Ser. No. 09/952,648, which is incorporated herein in its entirety.
  • assays which are used for measurement of cellular and enzymatic activities, both qualitatively and quantitatively, and in methods for diagnosing metastases, metastatic potential and inflammatory states, are performed with and without the addition of at least one of the compounds of the present invention to determine the activity of the compound.
  • Existing heparanase assays are taught in Goshen et al., 2 M OL . H UM . R EPROD .
  • the present invention comprises methods and compositions for the treatment and prevention of diseases or conditions that present or result from glycosidase activity.
  • Such methods comprise administration of compositions comprising compounds capable of modulating heparanase activity, such as compositions comprising compounds disclosed herein that inhibit heparanase activity.
  • Administration of such compounds that are effective in modulating heparanase activity are administered to humans and animals suspected of having or who have, for example, inflammatory conditions, autoimmune disease, or diabetic vasculopathy.
  • Effective amounts are administered to such humans and animals in dosages that are safe and effective, including, but not limited to, the ranges taught herein.
  • Routes of administration include, but are not limited to, those disclosed herein.
  • compositions comprising such compounds may be used in conjunction with other therapeutic agents, or in methods comprising steps such as altered patient activities.
  • One aspect of the present invention comprises methods and compositions comprising compounds of the present invention for the treatment and prevention of conditions or diseases that have as an aspect of the disease or condition, inflammation.
  • An aspect of the present invention is directed to methods and compositions comprising compounds that are effective in inhibiting inflammation, particularly inflammation associated with the accumulation or presence of glycated proteins or AGE.
  • the activity of modulating inflammation includes, but is not limited to, inhibiting inflammation and/or its associated cell activation by glycated proteins or AGE, blocking the glycation of proteins, blocking AGE interactions with receptors, blocking AGE-induced signaling or signaling-associated inflammatory responses, cytokine induction, synthesis, or release, AGE formation, or AGE cross-linking.
  • the present invention also provides compositions for and methods of treatment of biological conditions including, but not limited to, vascular complications of type I and type II diabetes and atherosclerosis.
  • Other inflammatory related diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, intraoccular inflammation, psoriasis, and asthma.
  • the compounds of the present invention have utility in inhibiting inflammation and/or its associated cell activation by glycated proteins or AGE.
  • Pharmacological inhibition of AGE-induced cell activation provides the basis for therapeutic intervention in many diseases, notably in diabetic complications and Alzheimer's disease.
  • Therapeutic approaches for inhibition of AGE-induced inflammation include, but are not limited to, blocking the glycation of proteins, blocking AGE interactions with receptors, and blocking AGE-induced signaling or signaling-associated inflammatory responses.
  • Compounds of the present invention that have at least the activity of modulating inflammation activity are shown in Table 6.
  • the compounds shown in this Table have the activity of modulating inflammation activity as measured by the assays taught herein.
  • N 4 -(3-Chloro-4-methoxy-phenyl)-6-(4-methanesulfonyl-phenyl)- pyrimidine-2,4-diamine 8.
  • the activity of the compounds of the present invention in inhibiting glycated protein- and AGE-induced inflammation can be determined using the assays described herein and in U.S. patent application Ser. No. 10/026,335, which is incorporated by reference herein in its entirety.
  • Such assays comprise measurement of the specific activity of biological components involved in a known cellular response.
  • the assays provide a measurable response in which the activity of the compounds is determined.
  • One assay comprises measurement of the effects of compounds on an inflammatory response by cells to the presence of a stimulating agent.
  • Yet another assay comprises endothelial cells that are stimulated by the addition of a glycated protein, the stimulating agent. The endothelial cells respond by producing specific cytokines.
  • the amount of cytokines produced are determined by measurement protocols known to those skilled in the art.
  • the compounds of the present invention are then added to the assay and the production of cytokines is measured. From the comparison of the assay without the compound with the assay with the compound, the biological effect of the compound can be determined.
  • the compound may have an inhibitory effect, a stimulatory effect, or no effect at all.
  • the amount and type of cytokine produced can be determined using immunological methods, such as ELISA assays.
  • the methods of the present invention are not limited by the type of assay used to measure the amount of cytokine produced, and any methods known to those skilled in the art and later developed can be used to measure the amount of cytokines produced in response to the stimulating agent and to the compound having unknown activity.
  • An aspect of the present invention comprises methods and compositions for the treatment of diseases, preconditions, or pathologies associated with inflammatory cytokines and other inflammation related molecules including, but not limited to IL-6, VCAM-1, or AGE-induced MCP-1 (monocyte chemoattractant protein 1).
  • Assays for determining the activity of compounds capable of modulating inflammation include those taught in U.S. patent application Ser. Nos. 10/026,335 and 09/969,013, which are both expressly incorporated by reference in their entireties.
  • the methods comprise addition of compounds of the present invention.
  • the effect of the compound on the baseline response is determined by comparing the amount of cytokine produced in the presence of the stimulating agent and the amount of cytokine produced in the presence of the stimulating agent and the compound of the present invention.
  • compounds that have inhibitory effects on the inflammation of the cells in the presence of glycated albumin are then used as therapeutic agents.
  • One or more compounds may be added to the screening assay. Combinations or mixtures of compounds can be added. Different amounts and formulations of the compounds are added to determine the effects on the screening assay.
  • the screening assay may also be used to determine stimulatory compounds or compounds that have no effects in the assay.
  • the present invention comprises methods and compositions for the treatment and prevention of disease, conditions and pathologies associated with inflammation.
  • Such methods comprise administration of compositions comprising compounds capable of modulating the activity of molecules associated with inflammation such as AGE or cytokines or other cellular factors, including release rates or activity, and include compositions comprising compounds disclosed herein with inflammation modulating activity.
  • Administration of such compounds that are effective in modulating inflammation are administered to humans and animals suspected of having or who have inflammatory diseases, for example, diabetic-induced vasculopathies, autoimmune diseases, renal insufficiency, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis.
  • Effective amounts are administered to such humans and animals in dosages that are safe and effective, including, but not limited to, the ranges taught herein. Routes of administration include, but are not limited to, those disclosed herein.
  • compositions comprising such compounds may be used in conjunction with other therapeutic agents or in methods comprising steps such as altered patient activities, including, but not limited to, changes in exercise or diet.
  • Tables 7-10 provide disclosure and references that relate the various physiological parameters and assays disclosed herein to general and specific diseases, disease states, and conditions.
  • the references and citations provided in these tables support the specification as fully enabled for treating or modulating all the diseases or conditions encompassed herein, based on the inhibiting activity of the compounds provided in the specification, and the predictive nature of the tests provided of the disclosed uses.
  • Tables 7-10 provide specific references that link the parameters measured in the key assays disclosed in the application with a specific physiology, pathophysiology, or medical condition.
  • Table 7 provides scientific references that demonstrate, among other things, the connection between TNF- ⁇ and IL-6 in rheumatoid arthritis, vascular inflammation, and atherosclerosis. For example, these references demonstrate the importance of TNF inhibition in preventing rheumatoid arthritis, the therapeutic benefit of IL-6 inhibition in rheumatoid arthritis as well as its importance in preventing rheumatoid arthritis, the role of AGE in different diabetic vascular diseases, and AGE inhibition as a therapeutic strategy for vascular complications.
  • Table 8 provides scientific references that demonstrate, among other things, the importance of HSPG in the prevention of atherosclerosis and diabetic vascular disease. For example, these references demonstrate that atherosclerotic vessels have reduced HSPG, and that cholesterol deposition is inversely correlated to HSPG content in the vessel.
  • Table 9 also provides scientific references that demonstrate, among other things, the connection between smooth muscle cell (SMC) proliferation in contributing to restenosis and atherosclerosis.
  • SMC smooth muscle cell
  • these references demonstrate that: smooth muscle proliferation contributes to unstable angina and restenosis; inhibition of SMC proliferation by LRP is important for atherosclerosis prevention; and the function of the SMC inhibitor, rapamycin, in preventing restenosis and vein graft disease.
  • Table 10 provides scientific references that demonstrate, among other things, the role of heparanase and TNF- ⁇ in promoting tumor angiogenesis and metastasis, as well as the use of inhibitors of heparanase and TNF- ⁇ in treating cancer.
  • these references demonstrate the role of heparanase inhibitors in treating tumor angiogenesis and metastasis, the role of TNF- ⁇ as a tumor-promoting agent, and the use of TNF- ⁇ inhibitors in the treatment of cancer.
  • the key assays described herein for screening the compounds in the present invention include, but are not limited to: a) the inhibition of smooth muscle cell (SMC) proliferation, that was used to identify, for example, compounds in Table 4; b) the induction of HSPG in smooth muscle cells; c) the induction of heparanase in endothelial cells; d) the inhibition of AGE-induced inflammatory response in endothelial cells as measured by IL-6 or other inflammatory cytokines, that was used to identify, for example, compounds in Table 6; and e) cytotoxicity effects of the disclosed compounds.
  • SMC smooth muscle cell
  • physiology, pathophysiology, or medical conditions disclosed herein include generically disclosed conditions and diseases such as, but are not limited to, unwanted cellular proliferation, inflammation mediated diseases, hyperproliferative diseases, and diseases involving a glycosidase.
  • diseases include, but are not limited to, restenosis, vascular occlusive diseases, arthritis, cancer, and the like.
  • HSPG Atherosclerosis Data show that et al, sulfated 1989; 9: 154-8 atherosclerotic vessels Ref 7 glycosaminoglycans have reduced HSPG and and cholesterol that cholesterol deposition content in normal and is inversely correlated to atherosclerotic human HSPG content in the aorta vessel Kruse R et Cholesterol-dependent Basic Res HSPG Atherosclerosis Data show that al changes of Cardiol. 1996 atherosclerotic vessels Ref 8 glycosaminoglycan Sep-Oct; have reduced HSPG and pattern in human aorta 91(5): 344-52 that cholesterol deposition is inversely correlated to HSPG content in the vessel
  • the compounds of the present invention may be used alone, in various combinations with one another, and/or in combination with other agents along with delivery devices to effectively prevent and treat the diseases described herein, though particular applications are found in vascular disease, and in particular, vascular disease caused by injury and/or by transplantation. Though this example focuses on vascular disease, provision of the compounds of the present invention with medical devices for treatment of the diseases and conditions capable of being treated with the compounds is contemplated by the present invention.
  • balloon angioplasty is a procedure utilized to increase blood flow through an artery and is the predominant treatment for coronary vessel stenosis.
  • the procedure typically causes a certain degree of damage to the vessel wall, thereby creating new problems or exacerbating the original problem at a point later in time.
  • exemplary aspects of the present invention will be described with respect to the treatment of restenosis and related complications following percutaneous transluminal coronary angioplasty and other similar arterial/venous procedures, including the joining of arteries, veins, and other fluid carrying conduits in other organs or sites of the body, such as the liver, lung, bladder, kidney, brain, prostate, neck, and legs.
  • the local delivery of a compound of the present invention and, in some aspects, along with other therapeutic agents, from a stent prevents vessel recoil and remodeling through the scaffolding action of the stent.
  • the activity of compound provided, with or without other therapeutic agents helps determine for which application, to treat which disease, the coated medical device is being administered.
  • compound-coated stents can prevent multiple components of neointimal hyperplasia or restenosis as well as reduce inflammation and thrombosis.
  • Local administration of a compound of the present invention and other therapeutic agents to stented coronary arteries may also have additional therapeutic benefit. For example, higher tissue concentrations of the compounds of the present invention and other therapeutic agents may be achieved utilizing local delivery rather than systemic administration.
  • reduced systemic toxicity may be achieved utilizing local delivery rather than systemic administration while maintaining higher tissue concentrations.
  • a single procedure may suffice with better patient compliance.
  • An additional benefit of combination therapeutic agent and/or compound therapy may be to reduce the dose of each of the therapeutic agents, thereby limiting toxicity, while still achieving a reduction in restenosis, inflammation, and thrombosis.
  • Local stent-based therapy is therefore a means of improving the therapeutic ratio (efficacy/toxicity) of anti-restenosis, anti-inflammatory, and anti-thrombotic therapeutic agents.
  • a compound of the present invention may be utilized to treat a wide variety of conditions utilizing any number of medical devices, or to enhance the function and/or life of the device.
  • intraocular lenses placed to restore vision after cataract surgery, are often compromised by the formation of a secondary cataract. The latter is often a result of cellular overgrowth on the lens surface and can be potentially minimized by combining one or more compounds of the present invention having activity that is effective in preventing unwanted cellular growth with the device.
  • shunts for hydrocephalus dialysis grafts
  • colostomy bag attachment devices colostomy bag attachment devices
  • ear drainage tubes ear drainage tubes
  • implantable defibrillators can also benefit from the combinations of the compounds of the present invention, possibly other pharmaceutical agents, and the devices.
  • any type of medical device may be coated in some fashion with at least one compound of the present invention, alone or as part of a therapeutic agent combination, which enhances treatment over the use of the device or therapeutic agent without combination with the compound.
  • the compounds of the present invention can be administered in combinational therapies with other therapeutic agents, and are not limited to only the other therapeutic agents disclosed herein.
  • the present invention also contemplates, in addition to various medical devices, the coatings on these devices may be used to deliver a compound of the present invention in combination with other therapeutic agents.
  • therapeutic agents can be administered through pharmeutical means or in association with medical devices and such therapeutic agents include, but are not limited to, antiproliferative/antimitotic agents including natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide, teniposide), antibiotics [e.g., dactinomycin (actinomycin D) daunorubicin, doxorubicin, and idarubicin], anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents such as G(GP) Ib/IIIa
  • stents may be utilized in accordance with the present invention, for simplicity, a limited number of stents will be described in exemplary aspects of the present invention. The skilled artisan will recognize that any number of stents may be utilized in connection with the present invention.
  • other medical devices may be utilized. For example, though stents are described, sleeves outside the vessels are also contemplated, as are other medical devices that can provide a substrate for administration for at least one of the compounds of the present invention.
  • a stent is commonly used as a tubular structure left inside the lumen of a duct to relieve an obstruction.
  • stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ.
  • a common method of expansion occurs through the use of a catheter-mounted, angioplasty balloon that is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
  • a stent may resemble an expandable cylinder and may comprise a fenestrated structure for placement in a blood vessel, duct or lumen to hold the vessel, duct or lumen open, more particularly for protecting a segment of artery from restenosis after angioplasty.
  • the stent may be expanded circumferentially and maintained in an expanded configuration that is circumferentially or radially rigid.
  • the stent may be axially flexible and when flexed at a band, for example, the stent avoids any externally protruding component parts.
  • the stent may be fabricated utilizing any number of methods.
  • the stent may be fabricated from a hollow or formed stainless steel tube that may be machined using lasers, electric discharge milling, chemical etching or other means.
  • the stent is inserted into the body and placed at the desired site in an unexpanded form.
  • expansion may be effected in a blood vessel by a balloon catheter, where the final diameter of the stent is a function of the diameter of the balloon catheter used.
  • a stent in accordance with the present invention may be embodied in a shape-memory material including, for example, an appropriate alloy of nickel and titanium or stainless steel.
  • Structures formed from stainless steel may be made self-expanding by configuring the stainless steel in a predetermined manner, for example, by twisting it into a braided configuration.
  • the stent after the stent has been formed it may be compressed so as to occupy a space sufficiently small as to permit its insertion in a blood vessel or other tissue by insertion means, wherein the insertion means include a suitable catheter, or flexible rod.
  • the stent Upon emerging from the catheter, the stent may be configured to expand into the desired configuration where the expansion is automatic or triggered by a change in pressure, temperature, or electrical stimulation.
  • a stent may be modified to comprise one or more reservoirs. Each of the reservoirs may be opened or closed as desired. These reservoirs may be specifically designed to hold the compound or compound/therapeutic agent combination to be delivered. Regardless of the design of the stent, it is preferable to have the compound or compound/therapeutic agent combination dosage applied with enough specificity and a sufficient concentration to provide an effective dosage in the affected area.
  • the reservoir size in the bands is preferably sized to adequately apply the compound or compound/therapeutic agent combination dosage at the desired location and in the desired amount.
  • the entire inner and outer surface of the stent may be coated with the compound or compound/therapeutic agent combination in therapeutic dosage amounts.
  • the coating techniques may vary depending on the compound or compound/therapeutic agent combination. Also, the coating techniques may vary depending on the material comprising the stent or other intraluminal medical device.
  • One or more compounds of the present invention and, in some instances, other therapeutic agents as a combination, may be incorporated onto or affixed to the stent in a number of ways.
  • the compound is directly incorporated into a polymeric matrix and sprayed onto the outer surface of the stent.
  • the compound elutes from the polymeric matrix over time and enters the surrounding tissue.
  • the compound preferably remains on the stent for at least three days up to approximately six months, and more preferably between seven and thirty days.
  • the polymeric matrix comprises two layers.
  • the base layer comprises a solution of poly(ethylene-co-vinylacetate) and polybutylmethacrylate.
  • the compound is incorporated into this base layer.
  • the outer layer comprises only polybutylmethacrylate and acts as a diffusion barrier to prevent the compound from eluting too quickly.
  • the thickness of the outer layer or topcoat determines the rate at which the compound elutes from the matrix. Essentially, the compound elutes from the matrix by diffusion through the polymer matrix. Polymers are permeable, thereby allowing solids, liquids and gases to escape therefrom.
  • the total thickness of the polymeric matrix is in the range from about one micron to about twenty microns or greater. It is important to note that primer layers and metal surface treatments may be utilized before the polymeric matrix is affixed to the medical device. For example, acid cleaning, alkaline (base) cleaning, salinization and parylene deposition may be used as part of the overall process described above.
  • the poly(ethylene-co-vinylacetate), polybutylmethacrylate, and compound solution may be incorporated into or onto the stent in a number of ways.
  • the solution may be sprayed onto the stent or the stent may be dipped into the solution.
  • Other methods include spin coating and plasma polymerization.
  • the solution is sprayed onto the stent and then allowed to dry.
  • the solution may be electrically charged to one polarity and the stent electrically charged to the opposite polarity. In this manner, the solution and stent will be attracted to one another. In using this type of spraying process, waste may be reduced and more precise control over the thickness of the coat may be achieved.
  • Drug-coated stents are manufactured by a number of companies including Johnson & Johnson, Inc. (New Brunswick, N.J.), Guidant Corp. (Santa Clara, Calif.), Medtronic, Inc. (Minneapolis, Minn.), Cook Group Incorporated (Bloomington, Ind.), Abbott Labs., Inc. (Abbott Park, Ill.), and Boston Scientific Corp. (Natick, Mass.). See e.g., U.S. Pat. No. 6,273, 913; U.S. Patent Application Publication No. 20020051730; WO 02/26271; and WO 02/26139, each expressly entirely incorporated herein by reference.
  • the present invention provides a composition comprising at least one compound as disclosed herein.
  • this invention provides a pharmaceutical composition, comprising:
  • a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof.
  • this invention provides a pharmaceutical composition, comprising:
  • a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof;
  • the pharmaceutical composition is in the form of a tablet, a capsule, a syrup, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, or a transdermal patch.
  • this invention provides a pharmaceutical composition, comprising:
  • a pharmaceutically acceptable additive selected from a carrier, an auxiliary, a diluent, an excipient, a preservative, a solvate, or any combination thereof;
  • the pharmaceutical compositions of the present invention can further comprise at least one of any suitable auxiliary such as, but not limited to, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like.
  • suitable auxiliaries are employed. Examples and methods of preparing such sterile solutions are well known in the art and can be found in well known texts such as, but not limited to, R EMINGTON'S P HARMACEUTICAL S CIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)).
  • Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and/or stability of the compound.
  • compositions for Oral Administration are provided.
  • a compound for oral administration in the form of a tablet or capsule, can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture.
  • suitable binders include, without limitation, starch; gelatin; natural sugars such as glucose or beta-lactose; corn sweeteners; natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose; polyethylene glycol; waxes; and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, and the like.
  • the invention further relates to the administration of at least one compound disclosed herein by the following routes, including, but not limited to oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic means, or transdermal means.
  • routes including, but not limited to oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabron
  • the pharmaceutical compositions can be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the daily dosage of the compositions can be varied over a wide range from about 0.0001 to about 1,000 mg per patient, per day. The range can more particularly be from about 0.001 mg/kg to 10 mg/kg of body weight per day, about 0.1-100 mg, about 1.0-50 mg or about 1.0-20 mg per day for adults (at about 60 kg).
  • the daily dosage of the pharmaceutical compositions can be varied over a wide range from about 0.01 to about 1000 mg per adult human per day.
  • the pharmaceutical compositions can be provided in the form of tablets containing from about 0.1 mg to about 1000 mg of the compound or 0.1, 0.2, 0.5, 1.0, 2.0, 5.0, 10.0, 15.0, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, or 1000 milligrams of the active compound for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 20 mg/kg of body weight per day. In one aspect, the range is from about 0.2 mg/kg to about 10 mg/kg of body weight per day.
  • the range is from about 0.5 mg/kg to about 10 mg/kg of body weight per day.
  • the compounds can be administered on a regimen of about I to about 10 times per day.
  • co-administration or sequential administration of the compounds of the present invention and other therapeutic agents can be employed, such as chemotherapeutic agents, immunosuppressive agents, cytokines, cytotoxic agents, nucleolytic compounds, radioactive isotopes, receptors, and pro-drug activating enzymes, which can be naturally occurring or produced by recombinant methods.
  • the combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active therapeutic agents simultaneously exert their biological activities.
  • any general structure presented also encompasses all conformational isomers, regioisomers, stereoisomers and tantiomers that may arise from a particular set of substituents.
  • the general structure also emcompasses all enantiomers, diastereomers, and other optical isomers whether in enantiomeric or racemic forms, as well as mixtures of stereoisomers, as the context requires.
  • the general structure also encompasses all pharmaceutically acceptable salts and prodrugs thereof.
  • Applicants' intent is to disclose or claim individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of sub-ranges encompassed therein.
  • Applicants disclose or claim a chemical moiety having a certain number of carbon atoms Applicants' intent is to disclose or claim individually every possible number that such a range could encompass, consistent with the disclosure herein.
  • R is selected independently from an alkyl group having up to 20 carbon atoms, or in alternative language a C 1 to C 20 alkyl group, as used herein, refers to an R group that can be selected independently from a hydrocarbyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, as well as any range between these two numbers for example a C 3 to C 8 alkyl group, and also including any combination of ranges between these two numbers for example a C 3 to C 5 and C 7 to C 10 hydrocarbyl group.
  • the molar ratio typically spans the range from about 0.1 to about 1.
  • the molar ratio can be selected from about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1.0:1, or about 1.1:1.
  • RT room temperature, typically ranging from about 20° C. to about 40° C.; aq, aqueous; min, minutes; h or hr, hours; g, grams; atm, atmosphere; conc., concentrated; MS or Mass Spec, mass spectroscopy/spectrometry; NMR, nuclear magnetic resonance; TMS, tetramethylsilane; R f , TLC retention factor; R t , HPLC retention time; HPFC, high pressure fraction collector; IR, infrared spectroscopy/spectrum; CH 3 CN, acetonitrile; N 2 , nitrogen; mg, milligrams; mmol, millimoles; mol, moles; nm, nanometers; HRMS, high resolution mass spectroscopy; and ° C., degrees Centigrade.
  • Abbreviations especially frequent in the NMR data are as follows: MHz, megahertz; br, broad; apt, apparent; s, singlet; d, doublet; t, triplet; q, quartet; dq, doublet of quartets; dd, doublet of doublets; dt, doublet of triplets; and m, multiplet.
  • step (i) A mixture of compound 3-(4-methoxy-phenyl)-3-oxo-propionic acid ethyl ester (69 g, 0.31 mol), obtained in step (i), guanidine carbonate (61.5 g, 0.34 mol) in ethanol (600 mL) was heated to reflux with vigorous stirring under nitrogen atmosphere for 6 to 12 hours. Ethanol was then removed under vacuum, the mixture was diluted with cold water (20 mL for 1 g of 3-(4-methoxy-phenyl)-3-oxo-propionic acid ethyl ester), and stirred for 10 minutes at temperature in the range of 20-40° C. The white solid separated out was isolated by filtration to afford the desired compound (55 g).
  • N 4 -(3-Chloro-4-methoxy-phenyl)-6-methyl-pyrimidine-2,4-diamine was prepared according to the procedure described in Example 1 (steps ii-iv) starting from ethylacetoacetate in place of 3-(4-methoxy-phenyl)-3-oxo-propionic acid ethyl ester.
  • Step (ii) Synthesis of 6-chloro-N 2 -(3-chloro-4-methoxy-phenyl)-N 4 -cycloheptyl-pyrimidine-2,4-diamine

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